[0001] The present application relates to abuse-deterrent pharmaceutical compositions.
[0002] Many pharmaceutical active ingredients, in addition to having excellent activity
in their appropriate application, also have potential for abuse, i.e. they can be
used by an abuser to bring about effects other than the medical ones intended. For
example, prescription opioid products are an important component of modern pain management.
However, abuse and misuse of these products have created a serious and growing public
health problem. One potentially important step towards the goal of creating safer
opioid analgesics has been the development of opioids that are formulated to deter
abuse. The development of these products is considered e.g. by the US FDA as a high
public health priority (see "
Abuse-Deterrent Opioids - Evaluation and Labeling"; Guidance for Industry FDA April
2015, FDA; "FDA Guidance").
[0003] Because opioid products are often manipulated for purposes of abuse by different
routes of administration or to defeat extended-release (ER) properties, most abuse-deterrent
technologies developed to date are intended to make manipulation more difficult or
to make abuse of the manipulated product less attractive or less rewarding. It should
be noted that these technologies have not yet proven successful at deterring the most
common form of abuse - swallowing a number of intact capsules or tablets to achieve
a feeling of euphoria. Moreover, the fact that a product has abuse-deterrent properties
does not mean that there is no risk of abuse. It means, rather, that the risk of abuse
is lower than it would be without such properties. Because opioid products must in
the end be able to deliver the opioid to the patient, there may always be some abuse
of these products.
[0004] In the FDA Guidance, abuse-deterrent properties are defined as those properties shown
to meaningfully deter abuse, even if they do not fully prevent abuse. The term abuse
is defined as the intentional, non-therapeutic use of a drug product or substance,
even once, to achieve a desirable psychological or physiological effect. Abuse is
not the same as misuse, which refers to the intentional therapeutic use of a drug
product in an inappropriate way and specifically excludes the definition of abuse.
The FDA Guidance uses the term "abuse-deterrent" rather than "tamper-resistant" because
the latter term refers to, or is used in connection with, packaging requirements applicable
to certain classes of drugs, devices, and cosmetics.
[0005] The science of abuse deterrence is relatively new, and both the formulation technologies
and the analytical, clinical, and statistical methods for evaluating those technologies
are rapidly evolving. The FDA Guidance identifies seven categories of abuse-deterrent
formulations:
- 1. Physical/chemical barriers - Physical barriers can prevent chewing, crushing, cutting,
grating, or grinding of the dosage form. Chemical barriers, such as gelling agents,
can resist extraction of the opioid using common solvents like water, simulated biological
media, alcohol, or other organic solvents. Physical and chemical barriers can limit
drug release following mechanical manipulation, or change the physical form of a drug,
rendering it less amenable to abuse.
- 2. Agonist/antagonist combinations - An opioid antagonist can be added to interfere
with, reduce, or defeat the euphoria associated with abuse. The antagonist can be
sequestered and released only upon manipulation of the product. For example, a drug
product can be formulated such that the substance that acts as an antagonist is not
clinically active when the product is swallowed, but becomes active if the product
is crushed and injected or snorted.
- 3. Aversion - Substances can be added to the product to produce an unpleasant effect
if the dosage form is manipulated or is used at a higher dosage than directed. For
example, the formulation can include a substance irritating to the nasal mucosa if
ground and snorted.
- 4. Delivery System (including use of depot injectable formulations and implants) -
Certain drug release designs or the method of drug delivery can offer resistance to
abuse. For example, sustained-release depot injectable formulation or a subcutaneous
implant may be difficult to manipulate.
- 5. New molecular entities and prodrugs - The properties of a new molecular entity
(NME) or prodrug could include the need for enzymatic activation, different receptor
binding profiles, slower penetration into the central nervous system, or other novel
effects. Prodrugs with abuse-deterrent properties could provide a chemical barrier
to the in vitro conversion to the parent opioid, which may deter the abuse of the
parent opioid. New molecular entities and prodrugs are subject to evaluation of abuse
potential for purposes of the Controlled Substances Act (CSA).
- 6. Combination - Two or more of the above methods could be combined to deter abuse.
- 7. Novel approaches - This category encompasses novel approaches or technologies that
are not captured in the previous categories.
[0006] Although there are already a number of proposals available based on the categories
1 to 5, above, there is still an unmet need to provide efficient combinations of these
methods and approaches and, especially, to provide novel approaches.
[0007] It is therefore the object of the present invention to provide a new approach and
technology for abuse-deterrent drug formulations.
[0008] Therefore, the present invention provides an abuse-deterrent pharmaceutical composition
comprising a drug with an enzyme-reactive functional group, wherein the drug has an
abuse potential, and an enzyme capable of reacting with the enzyme-reactive functional
group (hereinafter referred to as the "drug-processing enzyme"), wherein the drug
with the enzyme-reactive functional group is contained in the pharmaceutical composition
in a storage stable, enzyme-reactive state and under conditions wherein no enzymatic
activity acts on the drug.
[0009] The present invention provides a new category of abuse-deterrent strategy (a "novel
approach") which offers a practical toolbox for virtually all pharmaceutical compositions
where a risk for abuse is present or has to be assumed.
[0010] The abuse-deterrent principle is - for each and every drug - the same: the drug with
the abuse risk is combined together with one or more enzymes (optionally also with
necessary cofactors/cosubstrates/mediators) in the pharmaceutical preparation in a
storage stable (usually dry) state wherein the enzyme is activatable (i.e. providing
the enzyme in an enzyme-reactive state); but wherein the enzyme in the pharmaceutical
preparation is contained under conditions not allowing enzymatic activity act on drug.
Accordingly, there may be e.g. a spatial or reactional separation in the pharmaceutical
composition. This principle is therefore also specifically suited for drugs with a
high risk of being abused, such as opioids, but also tranquilizers (especially benzodiazepins),
stimulants and narcotics.
[0011] If the drug is administered as intended - e.g. by ingestion of a tablet - the enzyme
is inactivated (in case of orally administered compositions preferably by the acidic
environment in the stomach and/or proteolytically active enzymes present in the GI-tract).
If the drug is abused by trying to extract the active substance from such pharmaceutical
compositions, the enzyme becomes active and acts on the drug so as to process the
drug into another compound which is either completely unusable anymore or has - at
least - a lower abuse potential and therefore lowers the motivation for abuse (i.e.
making the pharmaceutical composition according to the present invention abuse-deterrent).
[0012] The present invention therefore provides the combination of a drug with an abuse
potential (hereinafter referred to as "the drug" or "the target drug") and a drug-processing
enzyme which is activated once the composition according to the present invention
is treated by abusive measures which aim at extracting the drug from the present pharmaceutical
composition. Whereas the compositions according to the present invention are usually
destined for oral administration, extraction of the drug in an abusive manner is usually
performed with the aim of providing (intravenously) injectable compositions. Drug-processing
enzymes are known in principle; virtually all enzymes which process the specific drug
with or without additional cofactors/cosubstrates/mediators are suitable in the composition
according to the present invention, if they can be appropriately manufactured and
can be provided in the composition with an activity (upon dissolving in aqueous solvents)
that is able to process the drug in an appropriate manner. Enzymes are known to catalyse
more than 5,000 biochemical reaction types. Enzymes according to the present invention
may require additional components so that they can act on the target drug according
to the present invention. For example, the enzymes according to the present invention
may need cofactors, cosubstrates and/or mediators. A mediator is usually a substance
that transfers electrons but acts as catalyst (or in a similar manner as a catalyst).
A cosubstrate participates (stoichiometrically) in the reaction (with the target drug).
Cofactors are "helper molecules" that assist the enzyme in the process of reacting
in the biochemical transformation with the drug. Accordingly, the present invention
applies reactions where an enzyme catalyses oxidation or reduction of mediator compound
which oxidizes or reduces the target drug; where an enzyme catalyses binding of co-substrates
to the drug; as well as where a second enzyme (or further enzymes) catalyses the transformation
of the activated drug.
[0013] Preferred drug-processing enzymes are those that are specific for the various functional
groups of the drug, i.e. the methoxy-group at C3 (the atom reference exemplified hereinafter
is made according to the oxycodone molecule; for other drugs of similar structure
(as many opioid target drugs) a person skilled in the art can immediately find the
corresponding functional group), the epoxy-group between C4 and C5, the oxo-Group
at C6, and the methyl group at the N-atom at position 17. These preferred enzymes
therefore include oxidoreductases (especially monooxygenases), transferases (such
as acetylases, sulfotransferases and glucuronosyltransferases), and hydrolases, especially
epoxide hydrolases. Preferred enzymes are therefore enzymes that catalyse O-demethylation
(especially O-demethylation or O-deethylation), N-dealkylation (especially N-demethylation
or N-deethylation), keto-reduction, N-oxidation, rearrangement of the ketone to an
ester (Baeyer-Villiger reaction; the ketone is transformed by a monooxygenase to an
ester (e.g. also a cyclic ketone to a lactone)), epoxy-hydroxylation, esterification,
de-amidation, peroxigenation, or dehalogenation of the drug or addition of molecules
(such as glucuronidation, sulfation and acetylation) to the drug. O-demethylation
primarily results in a transformation of the methoxy-group into a hydroxy-group, which
may then further react by addition of further molecules (including di- or polymerization)
or further oxidation. Further reaction may also be catalysed by a second enzyme. N-demethylation
primarily results in a secondary amine group, which may then further react by addition
of further molecules (including di- or polymerization) or further oxidation. Again,
further reaction may also be catalysed by a second enzyme. Keto-reduction results
in a transformation of the keto-group into a hydroxy-group, which may then further
react by addition of further molecules (including di- or polymerization) or further
oxidation. Again, further reaction may also be catalysed by a second enzyme. N-oxidation
leads to an N-oxide compound, which may either directly lead to an inactivation of
the drug or then further react by addition of further molecules (including di- or
polymerization). Epoxy-hydroxylation results in dihydrodiols (often: trans-dihydrodiols),
which may then further react by addition of further molecules (including di- or polymerization)
or further oxidation. Addition of molecules (such as sulfation, glucuronidation and
acetylation, but also including di- or polymerization) leads to products that are
often insoluble or are deprived of their abusive potential due to accelerated excretion
potential). In these reaction synthetic substrates (e.g. in glucoronidation) may be
added to enhance inactivation of the drug. Esterification are preformed by esterases
(for OH-groups) or trans-esterases (e.g. for pethidine). De-amidation can be performed
by amidases (EC 3.5.1.4) for example on fentanyl; peroxygenases (e.g. EC 1.11.2.1)
can react in a variety of P450 reactions, dehalogenases (such as EC 3.8.1) can react
on halogen containing target drugs, such as cebranopadol.
[0014] With such enzymes the target drug is processed to an inactive form or - at least
- to agents which are less active than the target drug and therefore are less attractive
for those who intend to abuse the pharmaceutical target drug compositions.
[0015] Examples of known drug-processing enzymes are NAD(P)(H)-dependent oxidoreductases,
such as the drug reducing enzymes from the aldo-keto reductase (AKR) superfamily,
especially AKR1C1 (20 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.149)), AKR1C2 and
AKR1C4. A specifically preferred oxycodone processing enzyme is 3-alpha-hydroxysteroid
3-dehydrogenase (EC 1.1.1.213). The NAD(P)(H)-dependent oxidoreductases transform
the target drug in the presence of NAD(P)H into its reduced degradation product. Another
preferred group of drug-processing enzymes are the keto-steroid reductases, such as
the 3-, 6- and 17-ketosteroid reductases.
[0016] According to a preferred embodiment, the drug-processing enzyme is a monooxygenase.
Monooxygenases have the ability to insert one oxygen atom into various organic substrates.
Molecular oxygen needs to be activated in order to carry out this type of reaction
and to do so, electrons are transferred from (in)organic cofactors to the molecular
oxygen. A wide range of oxidative reactions are catalysed by monooxygenases like hydroxylations
from aliphatic and aromatic compounds, epoxidations from alkenes, Baeyer-Villiger
oxidations, sulfoxidations, amine oxidations, selenide oxidations, halogenations,
phosphite ester oxidations and organoboron oxidations.
[0017] Monooxygenases are divided into the following families: Cytochrome P450 monooxygenases
or heme-dependent monooxygenases (EC 1.14.13, EC 1.14.14, EC 1.14.15) is the best
known and largest family of monooxygenases and mainly present in eukaryotic (mammals,
plants, fungi) as well as bacterial genomes and are able to hydroxylate non-activated
carbon atoms. Non-heme iron-dependent monooxygenases (EC 1.14.16) catalyse hydroxylation
and epoxidation reactions and utilize two iron atoms as cofactor. Enzymes that belong
to this family include alkene monooxygenases, phenol hydroxylases, membrane-bound
alkane hydroxylases as well as aromatic monooxygenases. Copper-dependent monooxygenases
(EC 1.14.17 and EC 1.14.18) represent a rather small family of enzymes, requiring
copper ions for hydroxylation of the substrates. Flavin-dependent monooxygenases (EC
1.13.12 and EC 1.14.13) are mostly found in prokaryotic genomes and are known to catalyse
epoxidations, Baeyer-Villiger oxidations and halogenations. Additionally, several
new types of monooxygenases were discovered that catalyse hydroxylations without being
cofactor-dependent (Cofactor-independent monooxygenases) but accept only a restricted
range of substrates. On the other hand the uncoupling reaction can be reversed; this
mechanism is present in the catalytic cycle of some monooxygenases to use hydrogen
peroxide to yield the oxidative enzyme intermediate. A more universal and well established
approach involves regeneration of NAD(P)H. Both chemical and enzyme based regeneration
is currently used. Chemical regeneration may use a rhodium-complex catalyst together
with formate as substrate which is oxidized to carbon dioxide. Thereby, electrons
are transferred NAD(P)
+ reducing the coenzyme. Likewise, enzymatic regeneration of NAD(P)H is well established
and is based on a large variety of NAD(P)
+-dependent dehydrogenases like formate dehydrogenase or glucose-6-phosphate dehydrogenase.
[0018] According to a further preferred embodiment, the drug-processing enzyme is a peroxygenase
(EC 1.11.1 und 1.11.2). Fungal unspecific peroxygenases (EC 1.11.2.1) are able to
oxyfunctionalise various compounds by transferring peroxide-borne oxygen to diverse
substrates. The catalyzed reactions are similar to those that are catalyzed by cytochrome
P450 monooxygenases and include hydroxylations of aliphatic compounds, epoxidations
of linear, branched and cyclic alkenes, dealkylations, oxidations of aromatic and
heterocyclic compounds as well as oxidations of organic hetero atoms and inorganic
halides.
[0019] Phenolic products are a product of aromatic peroxygenations and these phenols can
subsequently be subjects of coupling and polymerization reactions via their corresponding
phenoxyl radicals due to the peroxidative activity of the enzymes. These enzymes are
mostly found in Basidiomycota and Ascomycota (e.g.
Agrocybe aegerita, Coprinellus radians, Marasmius rotula) but also Mucoromycotina, Chytridiomycota , Glomeromycota as well as Oomycota whereas
no indication was found that they are present in plants, animals or prokaryotes. The
needed hydrogen peroxide can be produced in situ by a variety of oxidases like glucose
oxidase (EC 1.1.3.4), cellobiose dehydrogenase (EC 1.1.99.18) or lactate oxidase(EC
1.1.3.2), enzymes that produce H
20
2 upon oxidizing substrates like glucose, oligossacharides, polysaccharides, lactate
and others many of which are present in formulations.
[0020] Specifically preferred further enzymes that are used as drug-processing enzymes according
to the present invention include the following ones:
O-demethylation (C3): Cytochrome P450 (EC 1.14; + heme + an H-donor, such as NAD(P)H),
especially CYP2C subfamily; CYP2D6; unspecific monooxygenase (EC 1.14.14.1; + NAD(P)H),
Codeine 3-0-demethylase (CODM; EC 1.14.11.32; + 2-oxoglutarate (+O2)) ; thebaine 6-O-demethylase (T6ODM; EC 1.14.11.31; + 2-oxoglutarate (+O2)); peroxidases (EC 1.11.1 and EC 1.11.2; + H2O2), especially horseradish peroxidase (HRP, EC 1.11.1.7; + H2O2) and fungal unspecific peroxygenases (EC 1.11.2.1).
Preferably, O-demethylation is combined with further processing steps, because it
is possible that oxymorphone, alpha- and beta-oxymorphol or other oxymorphone-like
products can result in such O-demethylation of the target drug e.g. in case of oxycodone.
Since oxymorphone could have similar abuse-potential as the target drug, a further
step (i.e. processing by a further, oxymorphone-processing enzyme) may be provided,
such as a glucuronidation step.
N-demethylation (N17): CYP1-3 (all: EC 1.14.14.1; + heme + H-donor, such as NAD(P)H,
FAD, FMN, ferredoxin, etc.), preferably CYP3A, CYP1A, CYP2B, CYP2C and CYP2D, especially
CYP3A4, CYP3A5, CYP3A7, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6, especially CYP3A4
and CYP3A5. Peroxidases (EC 1.11.1 and EC 1.11.2; + H2O2), horseradish peroxidase (HRP, EC 1.11.1.7; + H2O2). N-demethylation may lead to products such as noroxycodone (if e.g. oxycodone is
transformed), noroxymorphone, alpha- and beta-noroxycodol, or similar products with
no or low abusive potential (although having a certain (but very low) opioid agonist
activity, but far less than oxycodone (also due to their poor uptake into the brain)).
Keto-reduction (C6): carbonyl reductase (NADPH) (EC 1.1.1.184; + NAD(P)H), such as
dihydromorphinone ketone reductase (DMKR; types I to V) and dihydrocodeinone ketone
reductase (DCKR, types I and II); additionally dehydrogenases such as morphine 6-dehydrogenase
(EC 1.1.1.218; + NAD(P)H). Keto-reduction may lead to products, such as alpha- and
beta-oxycodol, or nor-6-oxycodol, which have no (or only a weak) abusive potential.
N-oxidation (N): Flavin-containing monooxygenase (EC 1.14.13.8; + NAD(P), FAD).
Epoxy-hydroxylation: microsomal epoxide hydrolase (EC 3.3.2.9), epoxide hydratase
(EC 3.3.2.3 and 4.2.1.63), soluble epoxide hydrolase (EC 3.3.2.10).
Glucuronidation: UDP-glucuronosyltransferase (EC 2.4.1.17; + UDP-glucuronate), especially
UGT1 and UGT2 enzymes, such as UGT1.1, UGT2B7, bilirubin-glucuronoside glucuronosyltransferase
(EC 2.4.1.95; + UDP-glucuronate). In all cases synthetic functionalised co-substrates
may be used e.g. instead of UDP-glucuronate to better promote inactivation of the
target drug may be added.
Acetylation: ac(et)yltransferase (EC 2.3) and CoA-transferase (E.C. 2.8.3), especially
N-acetyltransferase (NAT, EC 2.3.1; usually + acetyl-Coenzyme A (ac-CoA)) and O-acetyltransferase
(OAT; EC 2.3.1; usually + ac-CoA).
Sulfation: sulfotransferases (EC 2.8.2), especially the human SULT transferases.
[0021] A further option to select suitable drug-processing enzymes is to select enzymes
disclosed to be effective and specific for a given reaction type (e.g. O-demethylation,
N-demethylation, keto-reduction, epoxy-hydoxylation, N-oxidation, or addition of molecules
(such as glucuronidation and acetylation)) from enzyme databases, such as the BRENDA
(BRaunschweig ENzyme DAtabase) enzyme portal (
http://www.brenda-enzymes.org). BRENDA is the main information system of functional biochemical and molecular enzyme
data and provides access to seven interconnected databases.
[0022] BRENDA contains 2.7 million manually annotated data on enzyme occurrence, function,
kinetics and molecular properties. Each entry is connected to a reference and the
source organism. Enzyme ligands are stored with their structures and can be accessed
via their names, synonyms or via a structure search.
[0023] FRENDA (Full Reference ENzyme DAta) and AMENDA (Automatic Mining of ENzyme DAta)
are based on text mining methods and represent a complete survey of PubMed abstracts
with information on enzymes in different organisms, tissues or organelles. The supplemental
database DRENDA provides more than 910 000 new EC number-disease relations in more
than 510 000 references from automatic search and a classification of enzyme-disease-related
information. KENDA (Kinetic ENzyme DAta), a new amendment extracts and displays kinetic
values from PubMed abstracts.
[0024] The integration of the EnzymeDetector offers an automatic comparison, evaluation
and prediction of enzyme function annotations for prokaryotic genomes. The biochemical
reaction database BKM-react contains non-redundant enzyme-catalysed and spontaneous
reactions and was developed to facilitate and accelerate the construction of biochemical
models.
[0025] The drug-processing enzymes often require co-factors, such as H and/or electron donors
and acceptors, such as NAD(P)H, FMN, FAD, ferredoxin, 2-oxoglutarate, hemes (CYP superfamily);
or donors for the groups to be added to the target drug (acetyl (such as ac-CoA),
glucoronate (such as UDP-glucuronate), etc.). These co-factors are also provided in
the composition according to the present invention, unless such factors are, in any
way, already present in a potentially abusive situation (e.g. if the composition is
dissolved in an aqueous solution, O
2 which is required for some of the oxidation reactions disclosed above, or H
2O needed for epoxy-hydroxylation will be available under such abusive conditions;
sometimes even the ions needed, provided they are contained in the extraction solvent).
In the present specification, co-factors needed for the specific enzymatic reaction
with the target drug (and provided in the present composition, e.g. as prosthetic
groups directly connected to the enzyme) are sometimes explicitly mentioned; however,
the person skilled in the art is well aware of the co-factors necessary and the conditions
suitable for obtaining a composition according to the present invention, wherein enzyme
activity is usually optimised to abusive circumstances, e.g. when the composition
is dissolved in water or an aqueous buffer.
[0026] In some embodiments, it can be preferred to provide a combination of enzymes (and
their respective co-factors) in the preparation according to the present invention.
For example, it can be preferred to add further processing enzymes, such as glucuronidases
and/or acetyltransferases to further process the target drug-products that emerge
from O-demethylation, N-demethylation, keto-reduction, epoxy-hydroxylation or N-oxidation,
e.g. by providing a glucuronidated/acetylated derivate at the newly created hydroxyl-group.
Such combinations may also be applied if the result of the drug-processing itself
represents a potential aim of abuse (as e.g. for oxymorphone).
[0027] If the drug-processing enzyme is a membrane-dependent enzyme, the enzyme may be provided
in liposomal form, preferably in the form of dry liposomes (in such cases, auxiliary
substances, such as sucrose or trehalose may be preferably added; see e.g.
Sun et al., Biophys. J 70 (1996): 1769-1776).
[0028] According to a specific embodiment, the pharmaceutical composition according to the
present invention comprises a further enzyme, preferably a further drug-processing
enzyme or an enzyme further processing the processed drug forms, especially laccase
(EC 1.10.3.2).
[0029] A specific embodiment of the present invention therefore additionally provides a
laccase in the present composition. Laccase can dimerise or polymerise (or initiate
or otherwise aid polymerisation of) the drug-processed molecules. Although laccase
itself is not directly an drug-processing enzyme (because it does not process the
target drug itself), laccase can be used with drug-processing enzymes disclosed above
to further enhance the abuse-deterrent character of the present compositions. Laccase
can also be used with electron mediators to directly oxidize the target drug or with
cosubstrates with certain functionalities (phenolic, aromatic amines, double bonds)
to form oligomers or polymers preventing abuse. Laccases are also suitable to create
hydrogels, specifically when employed with hydrogel-forming components, such as chitosan
and/or catechol or carboxymethylchitosan and/or vanillin. Laccases (EC 1.10.3.2; CAS
registry number 80498-15-3) are frequently described and analysed copper-containing
oxidase enzymes that are found in many plants, fungi, and microorganisms (
Riva, Trends in Biotechnology 24 (2006), 219-226). Laccases act on phenols and similar molecules, performing one-electron oxidations.
According to the BRENDA database, the systematic name of laccase is benzenediol:oxygen
oxidoreductase. Laccases are defined as a group of multi-copper proteins of low specificity
acting on both o- and p-quinols, and often acting also on aminophenols and phenylenediamine.
The semiquinone may react further either enzymatically or non-enzymatically.
[0030] Additionally, some non-laccase substrates can be oxidized by using mediators for
the reaction. When these well-established laccase mediators are oxidized by laccase
they generate strong oxidizing reactive species (radicals, radical quinones and quinones)
which can further react with non-laccase substrates. If the laccase oxidized mediator
is reduced back to its original compound, it is again re-oxidized by laccase to generate
reactive species which can again oxidize another molecule. Such laccase mediators
are able to oxidize molecules which cannot be oxidized directly by laccase. There
are many types of mediators used in laccase formulations including aromatic centered
mediators (ArOH; e.g. ferulic acid, syringaldehyde) and nitrogen centered mediators
(RNOH; e.g. violuric acid, 1-hydroxybenzotriazole.
[0031] Another strategy involves the use of co-substrates together with laccase. Co-substrates
are added to the reaction and they are oxidized by the laccase subsequently reacting
and forming covalent bonds with non-laccase substrates resulting in oligomers or polymers.
Generally many laccase substrates can act as cosubstrates to bind to non-laccases
substrates such as phenolics (catechol), aromatic amines, alkenes, etc..
[0032] Laccases play a role in the formation of lignin by promoting the oxidative coupling
of monolignols, a family of naturally occurring phenols. Laccases can be polymeric,
and the enzymatically active form can be a dimer or trimer. Other laccases, such as
the ones produced by the fungus
Pleurotus ostreatus, play a role in the degradation of lignin, and can therefore be included in the broad
category of lignin-modifying enzymes. Because laccase belongs to the oxidase enzyme
family it requires oxygen as a second substrate for the enzymatic action. Spectrophotometry
can be used to detect laccases, using the substrates ABTS (2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic
acid), syringaldazine, 2,6-dimethoxyphenol, and dimethyl-p-phenylenediamine. Activity
can also be monitored with an oxygen sensor, as the oxidation of the substrate is
paired with the reduction of oxygen to water.
[0033] The present invention provides the combination of the target drug with drug-processing
enzymes as a novel approach for abuse-deterrent pharmaceutical drug formulations.
The new strategy on which the present invention is based is the use of a drug-processing
enzyme (or an enzyme system) to convert drug into a non-active form (e.g. into a precipitated
or inactivated or less-active product) making it non-useable (e.g. by transforming
it into an inactive (or at least: less active) form or by making it impossible to
inject the drug with a syringe). On the other hand, if the target drug is administrated
as foreseen (e.g. orally), proteases from the body (or the total environment of the
stomach and the small intestine) deactivate the drug-processing enzyme and the target
drug can unfold its effect without being inactivated by the accompanying enzyme. For
an improved protease-degradability, the drug-processing enzymes may be modified by
the introduction of (additional) protease cleavage sites so as to increase the degradation
rate of these enzymes after exposure to such proteases.
[0034] A prerequisite of the abuse-deterrent strategy according to the present invention
is that during storage and before use the composition according to the present invention
containing a combination of the target drug and the drug-processing enzyme is kept
in an environment wherein the drug-processing enzyme does not (yet) react with the
target drug. This can e.g. be safeguarded by keeping (storing) both components under
conditions where the drug-processing enzyme is inactive or by spatial separation of
the two components. For example, if the composition is kept in a dry form, the drug-processing
enzyme cannot react with the target drug because such reaction requires aqueous conditions.
As soon as a dry composition according to the present invention is dissolved in water
(e.g. in order to extract the opioid drug for abuse), the drug-processing enzyme can
react with the target drug and enzymatically transforms the target drug into a molecule
that is not (ab-)usable anymore because of its degradation or because it is polymerised.
Another example for preventing the drug-processing enzyme to react on the target drug
is to spatially separate the target drug-processing enzyme from the target drug so
that - again - only after contact of the composition with water or a comparable solvent,
the drug-processing enzyme can react on the target drug. Such spatial separation can
e.g. be established by providing the drug-processing enzyme and the target drug in
different compartments of the pharmaceutical formulation, by providing specific coatings,
by separate granulation, etc..
[0035] On the other hand, the drug-processing enzyme in the compositions according to the
present invention must be reactive, e.g. once exposed to aqueous environment or to
other situations which are not in line with the administration routes or administration
activities intended (i.e. if an abuse is likely), it has to react with the accompanied
target drug to prevent or at least deter abuse of this drug.
[0036] The new abuse-deterrant strategy according to the present invention is in principle
applicable for any target drug that has a risk for abuse. For each of such drugs,
a suitable enzyme (or enzyme system) may be found according to the rationale given
in the present specification.
[0037] Preferred target drugs according to the present invention are those drugs with the
highest abuse potential, especially opioids, substituted amphetamines, barbiturates,
benzodiazepines (particularly flunitrazepam, oxazepam, alprazolam, lorazepam, diazepam
and clonazepam), cocaine, methaqualone, cannabis. Preferred opioids subjected to the
abuse-deterrent strategy according to the present invention are selected from the
group morphine, tapentadol, oxycodone, buprenorphine, cebranopadol, diamorphine (=heroin),
dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, methadone and levomethadone,
oxymorphone, pentazocine, pethidine, fentanyl, levorphanol and levomethorphane and
pharmaceutically acceptable salts, esters, prodrugs and mixtures thereof.
[0038] Other preferred target drugs may be selected from the group consisting of opiates,
opioids, tranquillizers, preferably benzodiazepines, stimulants and other narcotics.
The dosage form according to the invention is particularly suitable for preventing
abuse of opiates, opioids, tranquillizers, and other narcotics which are selected
from the group consisting of N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide(alfentanil),
5,5-diallylbarbituric acid (allobarbital), allylprodine, alphaprodine, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam),
2-diethylaminopropiophenone(amfepramone), (±)-[alpha]-methylphenethylamine (amphetamine),
2-([alpha]-methylphenethylamino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentylbarbituric
acid (amobarbital) anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital),
benzylmorphine, bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one
(bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
(brotizolam), 17-cyclopropylmethyl-4,5[alpha]-epoxy-7[alpha][(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol
(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate
(camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine
4-oxide (chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione
(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (clonazepam),
clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic
acid (clorazepate), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno [2,3-e][1,4]diazepin-2(3H)-one
(clotiazepam), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one
(cloxazolam), (-)-methyl-[3[beta]-benzoyloxy-2[beta](1[alpha]H,5[alpha]H)-tropane
carboxylate](cocaine), 4,5[alpha]-epoxy-3-methoxy-17-methyl-7-morphinen-6[alpha]-ol
(codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclorphan,
cyprenorphine, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (delorazepam),
desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate
(dextropropoxyphene), dezocine, diampromide, diamorphone, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(diazepam), 4,5[alpha]-epoxy-3-methoxy-17-methyl-6[alpha]-morphinanol(dihydrocodeine),
4,5[alpha]-epoxy-17-methyl-3,6[alpha]-morphinandiol (dihydromorphine), dimenoxadol,
dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
(dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
(estazolam), ethoheptazine, ethylmethylthiambutene, ethyl [7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethyl
loflazepate), 4,5a-epoxy-3-ethoxy-17-methyl-7-morphinen-6a-ol (ethylmorphine), etonitazene,
4,5[alpha]-epoxy-7[alpha]-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol
(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine), 7-[2-([alpha]-methylphenethylamino)ethyl]-theophylline)
(fenethylline), 3-([alpha]-methylphenethylamino)propionitrile (fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide
(fentanyl), 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (fludiazepam),
5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one (flunitrazepam),
7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one
(flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one
(halazepam), 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one
(haloxazolam), heroin, 4,5[alpha]-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone),
4,5[alpha]-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypethidine,
isomethadone, hydroxymethylmorphinan, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione
(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone),
(3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)),
(-)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (-)-17-methyl-3-morphinanol
(levorphanol), levophenacylmorphane, lofentanil, 6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one
(loprazolam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one
(lorazepam), 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one
(lormetazepam), 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol (mazindol),
7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam), N-(3-chloropropyl)-[alpha]-methylphenethylamine
(mefenorex), meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate),
meptazinol, metazocine, methylmorphine, N,[alpha]-dimethylphenethylamine (metamphetamine),
(±)-6-dimethylamino-4,4-diphenol-3-heptanone (methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone
(methaqualone), methyl [2-phenyl-2-(2-piperidyl)acetate](methylphenidate), 5-ethyl-1-methyl-5-phenylbarbituric
acid (methylphenobarbital), 3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon),
metopon, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine
(midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil), 4,5[alpha]-epoxy-17-methyl-7-morphinen-3,6[alpha]-diol
(morphine), myrophine, (±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10[alpha]-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6[alpha]H)-one
(nabilone), nalbuphene, nalorphine, narceine, nicomorphine, 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),
normorphine, norpipanone, the exudation from plants belonging to the species Papaver
somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (oxazepam),
(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one
(oxazolam), 4,5[alpha]-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone (oxycodone),
oxymorphone, plants and parts of plants belonging to the species Papaver somniferum
(including the subspecies setigerum) (Papaver somniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone
(pernoline), 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol
(pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid (pentobarbital), ethyl (1-methyl-4-phenyl-4-piperidinecarboxylate)
(pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine, pholcodeine,
3-methyl-2-phenylmorpholine (phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital),
[alpha],[alpha]-dimethylphenethylamine (phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one
(pinazepam), [alpha]-(2-piperidyl)benzhydryl alcohol (pipradrol), 1'-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4'-carboxamide
(piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,
methyl {3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(remifentanil),
5-sec-butyl-5-ethylbarbituric acid (secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric
acid (secobarbital), N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide
(sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (temazepam),
7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (tetrazepam),
ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine, cis and trans)),
tramadol, 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,
(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,
in each case optionally in the form of corresponding stereoisomeric compounds and
corresponding derivatives, in particular esters or ethers, and respective corresponding
physiologically acceptable compounds, in particular salts and solvates.
[0039] Specifically preferred opioids can be selected from the group consisting of opioids
comprising a phenolic hydroxy-group, such as morphine, tapentadol, hydromorphone,
etorphine, desomorphine, oxymorphone, buprenorphine, opioid peptides comprising a
phenylalanine residue, such as adrenorphin, amidorphin, casomorphin, DADLE ([D-Ala
2, D-Leu
5]-Enkephalin), DAMGO ([D-Ala
2, N-MePhe
4, Gly-ol]-enkephalin), dermorphin, endomorphin, morphiceptin, and TRIMU 5 (L-tyrosyl-N-{[(3-methylbutyl)amino]acetyl}-D-alaninamide);
oripavine, 6-MDDM (6-methylenedihydrodesoxymorphine), chlornaltrexamine, dihydromorphine,
hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378 (7,8-Dihydro-14-hydroxy-N-phenethylnormorphine),
heterocodeine, 7-spiroindanyloxymorphone, morphinone, pentamorphone, semorphone, chloromorphide,
nalbuphine, oxymorphazone, 1-iodomorphine, morphine-6-glucuronide, 6-monoacetylmorphine,
normorphine, morphine-N-oxide, cyclorphan, dextrallorphan, levorphanol, levophenacylmorphan,
norlevorphanol, oxilorphan, phenomorphan, furethylnorlevorphanol, xorphanol, butorphanol,
6,14-endoethenotetrahydrooripavine, BU-48 (N-Cyclopropylmethyl-[7α,8α,2',3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine),
buprenorphine, cyprenorphine, dihydroetorphine, etorphine, norbuprenorphine, 5'-guanidinonaltrindole,
diprenorphine, levallorphan, methylnaltrexone, nalfurafine, nalmefene, naloxazone,
naloxone, nalorphine, naltrexone, naltriben, naltrindole, 6β-naltrexol-d4, pseudomorphine,
naloxonazine, norbinaltorphimine, alazocine, bremazocine, dezocine, ketazocine, metazocine,
pentazocine, phenazocine, cyclazocine, hydroxypethidine (bemidone), ketobemidone,
preferably morphine, tapentadol, buprenorphine, especially morphine. An example of
an opioid drug with a phenolic amino group is anileridine. These aforementioned opioids
may e.g. processed by laccase as drug-processing enzyme.
[0040] Preferred pharmaceutical compositions according to the present invention comprise
as drug/drug-processing enzyme a combination selected from morphine/laccase, tapentadol/laccase,
oxymorphone/laccase, hydromorphone/laccase, pentazocine/laccase, buprenorphine/laccase,
levorphanol/laccase, and oxycodone/laccase/oxycodone-processing enzyme.
[0041] The present pharmaceutical composition can be formulated according to the intended
(non-abuse-deterrent) administration route, if necessary, adapted to the present invention
(e.g. when the drug-processing enzyme and the target drug are spatially separated).
Preferably, the pharmaceutical composition according to the present invention is provided
as a dose unit. It is therefore preferred to provide the present composition as a
tablet, a coat-core tablet, a bi-layer tablet, a multi-layer tablet, a sublingual
and a buccal tablet, a sublingual film, a capsule, a pellet, a MUPS (multiple unit
pellet system), a granulate, a powder, especially coated, sugar-coated and/or functionally
coated (e.g. enteric coated) forms thereof. Enteric coatings are specifically advantageous
for the prevention of premature inactivation of the drug-processing enzyme, i.e. before
the physiologic proteases act on the drug-processing enzyme. An enteric coating is
generally defined as a polymer barrier applied on oral medication for protecting drugs
from the acidity of the stomach. Enteric coatings are therefore usually stable at
the highly acidic pH found in the stomach, but break down rapidly at a less acidic
(relatively more basic; pH 7-9) pH in the intestine (i.e. after leaving the stomach).
Typical substances/materials used for such enteric coatings are shellac, cellulose
acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose
phthalate, and methacrylic acid ester copolymers, or zein, for example, as well as
hydrophobic or hydrophilic polymers and mixtures of such substances, if appropriate.
Hydrophobic polymeric coatings include acrylic polymer, acrylic copolymer, methacrylic
polymer or methacrylic copolymer, including Eudragit
® L100, Eudragit
® L100-55, Eudragit
® L 30D-55, Eudragit
® S100, Eudragit
® 4135F, Eudragit
® RS, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate
copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamine copolymer,
polymethyl methacrylate, polymethacrylic acid anhydride, polymethacrylate, polyacrylamide,
polymethacrylic acid anhydride and glycidyl methacrylate copolymers, an alkylcellulose
such as ethylcellulose, methylcellulose, carboxymethyl cellulose, hydroxyalkylcellulose,
hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose phthalate, and
hydroxypropyl methylcellulose acetate succinate, cellulose acetate butyrate, cellulose
acetate phthalate, and cellulose acetate trimaleate, polyvinyl acetate phthalate,
polyester, waxes, shellac, zein, or the like. The coating can also include hydrophilic
materials such as a pharmaceutically-acceptable, water-soluble polymer such as polyethylene
oxide (PEO), ethylene oxide-propylene oxide co-polymers, polyethylene-polypropylene
glycol (e.g. poloxamer), carbomer, polycarbophil, chitosan, polyvinyl pyrrolidone
(PVP), polyvinyl alcohol (PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose
(HPC), hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methylcellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl
methylcellulose, polyacrylates such as carbomer, polyacrylamides, polymethacrylamides,
polyphosphazines, polyoxazolidines, polyhydroxyalkylcarboxylic acids, alginic acid
and its derivatives such as carrageenate alginates, ammonium alginate and sodium alginate,
starch and starch derivatives, polysaccharides, carboxypolymethylene, polyethylene
glycol, natural gums such as gum guar, gum acacia, gum tragacanth, karaya gum and
gum xanthan, , gelatin or the like.
[0042] Preferred enteric coating materials are methyl acrylate-methacrylic acid copolymers,
cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl
methyl cellulose acetate succinate, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic
acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate and zein.
[0043] A further embodiment of the pharmaceutical composition according to the present invention
is a coated composition wherein the coat comprises the drug-processing enzyme. The
drug-processing enzyme acts on the target drug when the coated composition is dissolved
in aqueous liquids (for extracting the drugs (opioids)), whereas the drug-processing
enzyme is immediately destroyed or inactivated after ingestion (according to the prescribed
(oral) administration route) in the stomach or in the intestine.
[0044] A specifically preferred embodiment is a composition wherein the drug-processing
enzyme is coated so as to keep the drug-processing enzyme inactive on the target drug
as long as the planned administration route is followed, i.e. which keeps the activity
of the drug-processing enzyme from the target drug while being coated, e.g. until
excretion of the (still coated) drug-processing enzyme by the patient, whereas abuse
activity destroys the coat so that the drug-processing enzyme immediately acts on
the target drug. For example, the drug-processing enzyme may be coated by one or more
of the aforementioned substances/materials used for enteric coatings, e.g. Eudragit
® L 30D-55 or Kollicoat
® MAE 30D. Specifically preferred examples of such film-coatings or sequestering materials
are Eudragit
® RS (30D), Eudragit
® NE 30 D; ethylcellulose, polymethacrylates (all disclosed in
Rowe et al. (Eds.) "Handbook of Pharmaceutical Excipients" 6th Ed. (2009), Pharmaceutical
Press, pages 262ff., 525 ff.); or the substances used in other opioid compositions for coating opioid
antagonists (see e.g.
EP 2 034 975 B1,
US 8,465,774 B2, and
WO 2004/026283 A1), except, of course and self-understanding, substances that have a degradation risk
by drug-processing enzyme activity (e.g. because they contain a group that is converted
by the drug-processing enzyme provided in the composition according to the present
invention).
[0045] The pharmaceutical composition preferably contains the target drug in the amount
foreseen in the non-abuse-deterrent original composition. Accordingly, the target
drug is preferably contained in an amount of 0.1 to 5.000 mg, preferably 0.5 to 1.000
mg, especially 1 to 500 mg, per dosage unit. Currently marketed pharmaceutical target
drug preparations contain 2.5, 5, 7.5, 10, 15, 20, 30, 40, 80, 120 or 160 mg, e.g.
as salt form, such as the hydrochloride. Preferred amounts of the target drug in such
single dosage units may therefore be provided from 0.5 to 500 mg, especially from
1 to 200 mg. Depending on the formulation and the expected activity of the drug-processing
enzyme during normal administration, also an increase of the amount of the target
drug may be provided (compared to the non-abuse-deterrent original composition, i.e.
to the pharmaceutical formulation of the target drug without the abuse-deterrent features)
e.g. to compensate possible loss of drug activity (if such minor loss of activity
is likely or cannot be completely excluded).
[0046] The amount of the drug-processing enzyme in the present pharmaceutical composition
can be adjusted mainly based on the amount of the target drug and the formulation
details. Illustrative examples to determine the activity of preferred drug-processing
enzymes are listed in the example section.
[0047] More specifically, the amount of the drug-processing enzyme in the present pharmaceutical
composition can be adjusted mainly based on the amount of drug, the reactivity of
the enzyme and the formulation details. For example, the drug-processing enzyme may
be added in the composition according to the present invention in an amount of 0.1
to 10.000 units. According to a preferred embodiment (e.g. if laccase is used as drug-processing
enzyme), laccase is contained in an amount of 1 to 1.000 units, preferably 10 to 100
units. There are several ways to determine laccase activity. For the present invention,
activities are determined by monitoring the oxidation of ABTS spectrophotometrically
at 420 nm (ε= 11.4 mL µmol
-1 cm
-1) at 25°C in 100 mM sodium phosphate buffer (pH 7). The enzyme activity is expressed
in Units, whereas one Unit (U) is defined as the amount of enzyme that catalyses the
conversion of 1 µmole of ABTS per minute (1 U = µmol min
-1) (hereinafter referred to as the "laccase test according to the present invention").
[0048] Although the present invention provides a completely new strategy for abuse-deterrent
drugs, the present novel approach is also combinable with other abuse-deterrent strategies,
e.g. the ones that have been identified in the FDA Guidance 2015 or in
Schaeffer, J. Med. Toxicol. 8 (2012), 400-407. Accordingly, the pharmaceutical composition according to the present invention preferably
comprises a further abuse-deterrent feature, for example a feature selected from the
group consisting of: a physical or chemical barrier, especially increased tablet hardness,
a (drug-processing enzyme-insensitive) drug antagonist, an aversion component, an
abuse-deterrent delivery system and a prodrug. Provision of a physical barrier, especially
increased tablet hardness, or an aversion component, especially a gelling agent and/or
a non-gelling viscosity-increasing agent (e.g. λ-carrageenan) or, e.g. an emetic or
a nasal irritant, is specifically preferred. For example, the present composition
can be provided as a formulation with a resistance of more than 400 N, especially
more than 500 N, as prescribed in the European Pharmacopeia (
Ph.Eur.8 (2014) 2.9.8). Further examples for abuse-deterrent features combinable with the present invention
are the provision of discrete mechanically reinforcing particles (
WO 2012/061779 A1), of materials that are both hydrophilic and hydrophobic (
WO 2012/112952 A1), of an acid soluble ingredient (a cationic polymer) with a buffering ingredient
(
US 9,101,636 B2), of a monolithic solidified oral dosage form prepared by a thermal process (
US 2008/0075771 A1), of an emetic or a nasal irritant (
US 2008/075771 A1), of an extruded formulation (
US 2015/0057304 A1) or of amorphous or polymeric organic acid salts of the opioid (
US 2015/016835 A1), etc..
[0049] According to a preferred embodiment the pharmaceutical composition comprises a matrix
containing 1 to 80 wt.% of one or more hydrophobic or hydrophilic polymers, preferably
a matrix comprising agar, alamic acid, alginic acid, carmellose, carboxymethylcellulose
sodium, carbomer (such as Carbopol
® carrageenan, chitosan, especially carboxymethylchitosan, catechol, copovidone, dextrin,
gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methacrylic acid copolymer, methylcellulose derivatives, microcrystalline
cellulose, polyacrylic acid, polyalkylene oxide, especially polyethylene glycol, polyvinyl
alcohol, polyvinyl acetate, povidone, propylene glycol alginate, a polyvinylcaprolactam-polyvinyl
acetate-polyethylene glycol graft co-polymer, pullulan, silicon dioxide, sodium alginate,
starch, vinylpyrrolidone-vinyl acetate copolymers, xanthan gum; or of non-polymer
matrix formers like microcrystalline wax, fatty alcohols and fatty acids like stearyl
alcohol, cetyl stearyl alcohol, stearic acid, palmitic acid or salts and mixtures
thereof, mono-, di- and triglycerides of saturated fatty acids with a chain length
between 16 and 22 carbon atoms and a mixture of such mono- di- and triglycerides,
respectively.
[0050] According to a preferred embodiment of the present invention, the pharmaceutical
composition comprises a hydrogel-forming component and/or suitable crosslinkers which
allows the generation of insoluble crosslinked hydrogels of the drug once the drug-processing
enzyme is activated by abusive steps (optionally a laccase as disclosed above may
also contribute to such crosslinking). Preferred hydrogel-forming components are chitosan
and carboxymethylchitosan; preferred crosslinkers are phenolic crosslinkers, especially
catechol and vanillin. Preferred examples of such hydrogel/crosslinker compositions
are compositions comprising chitosan and catechol or compositions comprising carboxymethylchitosan
and vanillin.
[0051] The pharmaceutical composition according to the present invention is preferably a
storage stable composition, preferably by comprising less than 5%, especially less
than 1%, drug-processing enzyme-processed target drug degradation products after 6
month storage at 25°C under dry conditions.
[0052] In general, the drug-processing enzymes should be acid-labile so that their activity
in the present composition is immediately inactivated as soon as the drug-processing
enzyme is in contact with the stomach fluid and/or the intestine environment of the
patient to whom the composition is administered.
[0053] The present pharmaceutical composition can be provided as a modified release composition,
especially a prolonged release composition. The term "modified form" is meant to include
accelerated release, controlled release, and sustained release forms. Certain release
forms can be characterized by their dissolution profile. "Dissolution profile", means
a plot of amount of active ingredient released as a function of time (Ph.Eur.
8 (2014) 2.9.3). The dissolution profile can be measured utilizing the Drug Release
Test <724>, which incorporates standard test USP 26 (Test <711>) of the US Pharmacopeia.
A profile is characterized by the test conditions selected. Thus, the dissolution
profile can be generated at a preselected apparatus, shaft speed, temperature, volume,
and pH of the dissolution media. A first dissolution profile can be measured at a
pH level approximating that of the stomach. A second dissolution profile can be measured
at a pH level approximating that of one point in the intestine or several pH levels
approximating multiple points in the intestine. A highly acidic pH may simulate the
stomach and a less acidic to basic pH can simulate the intestine. By the term "highly
acidic pH" it is meant a pH of about 1 to about 4. By the term "less acidic to basic
pH" is meant a pH of greater than about 4 to about 7.5, preferably about 6 to about
7.5. A pH of about 1.2 can be used to simulate the pH of the stomach. A pH of about
6.0 to about 7.5, preferably about 7.5 can be used to simulate the pH of the intestine.
[0054] In contrast to modified release, "immediate release" is the conventional or non-modified
release form in which greater than or equal to about 50% or more preferably about
75% of a drug according to the present invention is released e.g. within two hours
of administration, preferably within one hour of administration, especially within
30 min of administration. By "controlled release" a dosage form is meant in which
the drug release is controlled or modified over a period of time. Controlled can mean,
for example, accelerated, sustained, delayed or pulsed release at a particular time.
Alternatively, controlled can mean that the drug release is extended for longer than
it would be in an immediate release dosage for, i.e., at least over several hours.
[0055] "Delayed release" indicates that there is a time-delay before significant plasma
levels of the drug are achieved. A delayed release formulation according to the present
invention avoids an initial burst of the drug, or can be formulated so that drug release
in the stomach is avoided. A "pulsed release" formulation can contain a combination
of immediate release, sustained release, and/or delayed release formulations in the
same dosage form. A "semi-delayed release" formulation is a "pulsed released formulation
in which a moderate dosage is provided immediately after administration and a larger
dosage some hours after administration.
[0056] The terms "sustained release" or "extended release" are meant to include the release
of the drug at such a rate that blood (e.g. plasma) levels are maintained within a
therapeutic range but below toxic levels for at least about 8 hours, preferably at
least about 12 hours, especially at least 24 hours (specifically preferred for 1 per
day dosage regimen) after administration at steady-state. The term "steady-state"
means that a plasma level for a given drug has been achieved and which is maintained
with subsequent doses of the drug at a level which is at or above the minimum effective
therapeutic level and is below the minimum toxic or overdose plasma level for a given
drug. Most of the polymeric matrices and non-polymer matrix formers mentioned above
have the capacity to deliver prolonged or sustained release capacity for a given drug
in the formulation according to the present invention.
[0057] According to a preferred embodiment, the pharmaceutical composition according to
the present invention comprises the target drug alone (as the only effective ingredient)
or in combination with other pharmaceutically active ingredients, preferably in combination
with a non-opioid analgesic, especially with ibuprofen, diclofenac, naproxen, paracetamol
and acetyl-salicylic acid.
[0058] In a preferred embodiment, the enzyme in the pharmaceutical composition essentially
does not act on the drug in vivo when the composition is swallowed intact.
[0059] Preferably, the enzyme in the pharmaceutical composition according to the present
invention is present in the composition in an essentially non-releasable form when
the composition is swallowed intact.
[0060] According to a preferred embodiment of the present invention the enzyme in the present
pharmaceutical composition is deactivated in vivo.
[0061] According to a further aspect, the present invention also relates to a method for
manufacturing a pharmaceutical composition according to the present invention comprising
the steps of mixing the target drug or a pharmaceutically acceptable salt, hydrate,
solvate, ester or prodrug thereof with the drug-processing enzyme and finishing the
mixture to a pharmaceutical composition. Alternatively, the method for manufacturing
the pharmaceutical composition according to the present invention comprises the steps
of providing the target drug or a pharmaceutically acceptable salt, hydrate, solvate,
ester or prodrug thereof and the drug-processing enzyme in separated form and finishing
the separated components to a pharmaceutical composition.
[0062] According to another aspect, the present invention provides a composition comprising
the target drug and a hydrogel-forming component and/or a crosslinker. The hydrogel-forming
component and/or the crosslinker allow the generation of insoluble crosslinked molecules,
especially as hydrogel, of the drug once the pharmaceutical composition is mixed with
an aqueous mixture in the process of abusive steps. Preferred hydrogel-forming components
are chitosan and carboxymethylchitosan; preferred crosslinkers are phenolic crosslinkers,
especially catechol and vanillin. Preferred examples of such hydrogel/crosslinker
compositions are composition comprising chitosan and catechol or compositions comprising
carboxymethylchitosan and vanillin.
[0063] Preferably, the compositions according to the present inventions are provided as
hydrogels. This involves the inclusion of another abuse deterrent approach, namely
to create a system which changes the rheological properties of the reaction solution,
i.e. the formation of a hydrogel. Hydrogels are very viscous and as a consequence,
the drawing up with a needle is not possible.
[0064] The present invention is further illustrated by the following examples and the figures,
yet without being restricted thereto.
Fig. 1 shows the strategy of the present invention, exemplified by the example of
morphine as drug. The abuse deterrent morphine/laccase system according to the present
invention either converts morphine into a precipitated product or creates in combination
with additives a hydrogel with which it is not possible anymore to inject the drug
with a syringe. If the drug is administrated as foreseen, proteases from the body
deactivate the laccase and the drug unfolds its effect.
Fig. 2 shows the opioids that are investigated in the examples (morphine (left), tapentadol
(middle) and oxycodone (right)).
Fig. 3 shows laccase oxidation of morphine with Myceliophthora thermophila (MtL) (violet)
and Trametes villosa (TvL) (green).
Fig. 4 shows laccase oxidation of tapentadol with MtL (violet) and TvL (green).
Fig. 5 shows laccase oxidation of oxycodone with MtL (green) and TvL (violet).
Fig. 6 shows a TLC of morphine after enzymatic conversion at different time points
compared to morphine as reference (first lane).
Fig. 7 shows a TLC of tapentadol after enzymatic conversion at different time points
compared to tapentadol as reference (first lane).
Fig. 8 shows an FTIR of morphine precipitate (red line: morphine reference, blue line:
precipitated morphine polymer)
Fig. 9 shows HPLC measurement of the enzymatically oxidized morphine.
Fig. 10 shows GC-MS spectra of morphine after enzymatic conversion.
Fig. 11 shows GC-MS spectra of morphine out of a GC-MS database library; comparison
of the measured spectrum to the database spectrum.
Fig. 12 shows the conversion of morphine by laccase, detected by GC-MS.
Fig. 13 shows the chitosan-catechol-morphine hydrogel.
Fig. 14 shows the carboxymethylchitosan-morphine hydrogel.
Fig. 15 shows the strategy of the present invention. The abuse deterrent oxycodone/oxycodone-processing
enzyme system according to the present invention either converts oxycodone into a
processed oxycodone derivative with no or low abusive potential or creates in combination
with additives a hydrogel with which it is not possible anymore to inject the drug
with a syringe. If oxycodone is administrated as foreseen, proteases from the body
(and the conditions in the stomach and in the small intestine) deactivate the oxycodone-processing
enzyme and oxycodone unfolds its effect.
Fig. 16 shows the enzymatic conversion of oxycodone to a partly precipitated product
Examples:
I.: Laccase for use in abuse-deterrent opioid formulations
[0065] Opioids are an important component of modern pain management, though the abuse and/or
misuse of those drugs has created a growing public health problem. To counteract this
problem, there is a strong demand for new technologies for preventing the abuse of
opioids. This project therefore tries to approach this problem with a very unique
way based on using enzymes.
[0066] The potential of enzymes to polymerize opioids, thereby preventing abuse were investigated.
These enzymes will not be active when opioids are administrated correctly. These possibilities
are thoroughly investigated by the present project.
[0067] In the present example, the development of an appropriate enzyme system to eliminate
opioids from solution is shown. Moreover, optimized reaction conditions for effective
conversion of the opioid solution preventing administration through injection are
provided. Finally, the function of the system is verified by showing the inactivation
of the opioid destroying enzymes proteolytically when the drugs are administered as
foreseen.
1. Materials
[0068] The opioids that are investigated were morphine, tapentadol and oxycodone as shown
in Figure 2.
[0069] Two different laccases were used to achieve elimination of opioids - one of them
originated from Trametes villosa (TvL), the other one from Myceliophthora thermophila
(MtL).
2. Oxygen Measurements
[0070] To determine whether the laccases act on any of the given opioids (morphine, tapentadol,
oxycodone), an optical oxygen sensor was used. Laccases use oxygen as electron acceptor,
consequently the oxygen concentration decreases upon substrate oxidation.
[0071] The conditions for the following reactions are shown in Table 1:
Table 1: Conditions for oxygen measurement of laccase catalysed oxidation of opioids
Enzyme (Laccase) |
10 U/ml |
Substrate |
2 mg/ml |
Solvent |
Distilled water |
Temperature |
Room temperature |
[0072] In Figure 3 the oxidation of morphine by two different laccases namely from Myceliophthora
thermophila (MtL) and Trametes villosa (TvL) is shown. The blue and red lines represent
the two blanks, blue with distilled water and enzyme, and red distilled water with
morphine. The violet and green lines represent the two reactions with the enzymes
(violet: MtL, green: TvL). After approx. 5 minutes there is a clear decrease in the
oxygen concentration in solution, meaning that the laccases are converting morphine
to a reaction product. Additionally, the two solutions turned cloudy which means the
reaction product precipitated. There was no significant difference between the two
enzymes.
[0073] In Figure 4 the oxidation of tapentadol by MtL (violet) and TvL (green) is shown.
The decrease of oxygen with MtL is much slower compared to the decrease of oxygen
with TvL. This could be because TvL has a much higher redox potential than the MtL.
The different curves also show that the specificity of the two enzymes is very different
on tapentadol. TvL converts tapentadol better which is indicated by the slope of the
curve as well as the fact that the curve in the case of TvL drops to almost 0% oxygen.
[0074] In Figure 5, the oxidation of oxycodone is shown. All of the curves look similar
indicating that the two used enzymes are not capable of converting oxycodone. The
cause for that is the missing phenolic - OH group in oxycodone (shown in Figure 2),
which is needed by laccases.
3. Thin Layer Chromatography
[0075] The reactions of morphine and tapentadol were also analysed by thin layer chromatography
and are shown in Figure 6 and 7.
[0076] Figure 6 shows the conversion of morphine. The first lane represents morphine as
a reference, whereas the other lanes show samples that were taken at different time
points (2, 10, 30, 60, 120 minutes). After only 2 minutes, 2 new dots are appearing
on the TLC plate, indicating that a new product is formed out of the enzymatic reaction
with morphine. The morphine reference dot disappears after 30 minutes, which indicates
that all of the morphine is converted. The same procedure is shown in Figure 7 for
tapentadol. The conversion of tapentadol is much slower, but there is also a new dot
appearing after 2 minutes and the tapentadol dot is disappearing after 120 minutes.
4. Analysis of the precipitated product
[0077] As mentioned above the reaction product of morphine precipitated, consequently the
next part was the analysis of this precipitate. The following conditions were used
for the reaction (Table 2).
Table 2: Conditions for the analysis of the morphine precipitate that is formed upon
the enzymatic reaction with MtL
Enzyme |
20 U/ml |
Substrate |
20 mg/ml |
Solvent |
Distilled water |
Temperature |
Room temperature |
[0078] After 24 hours, the reaction mixture was centrifuged for 15 min at 16.100 rcf (relative
centrifugal force). The supernatant was discarded and the remaining precipitate was
lyophilized overnight. On the next day the dry precipitate was analyzed via FTIR as
shown in Figure 8. The red line shows morphine, the blue line the precipitated reaction
product. It can be seen that there are new peaks arising and other peaks decreasing
due to the polymerization reaction of the morphine.
[0079] For further analysis a solubility test of the precipitate was performed. As indicated
in Table 3, the results for the solubility test were ambivalent. In none of the used
solvents the precipitate was soluble, most likely meaning that a high molecular weight
product was formed upon the enzymatic reaction. This is desirable for the main goal
of the project, but for further analysis a soluble compound is necessary.
Table 3: Solubility tests of the precipitate formed upon the laccase-catalyzed oxidation
of morphine
Solvent |
Concentration of morphine precipitate [mg/ml] |
Solubility |
Acetonitrile |
0.4 |
- |
THF |
0.3 |
- |
Diethylether |
0.4 |
- |
Toluene |
0.4 |
- |
Hexane |
0.3 |
- |
100 mM Citrate buffer pH4 |
1 |
∼ |
100 mM Phosphate buffer pH3 |
1 |
∼ |
50 mM Ammonium formate buffer pH3 |
0.001 |
∼ |
5. Analysis of the precipitated product
[0080] To address the second task - the changing of the rheological properties of the reaction
mixture - different additives were added to increase the viscosity of the solution.
The tested additives are shown in Table 4 and were mixed to the reaction as stated.
Most of the chosen additives are already used in pharmaceutical applications. The
desired increase in viscosity was only achieved when using hydroxypropylmethylcellulose
(HPMC).
Table 4: Additives for the enzymatic morphine reaction to increase the viscosity
Additive |
Ratio/concentration |
Troubleshooting |
Increased viscosity |
Ferulic acid |
1:1 |
|
- |
Catechol |
1:1 |
toxic |
- |
Starch |
1:1 |
solubility |
- |
Polyvinylpyrrolidone (PVP) |
50 mg/ml |
solubility |
- |
Polyethylenglycol (PEG6000) |
50 mg/ml |
|
- |
HPMC |
100 mg/ml |
time |
+ |
Catechin |
1:1 |
|
- |
Neohesperidin dihydrochalcon |
1:1 |
|
- |
6. Measurements of enzymatic conversion using HPLC & GC
[0081] The kinetic of the enzymatic conversion of morphine was analyzed via HPLC and GC
analysis.
[0082] Samples were taken at different time points (0, 2, 5, 10, 15, 30 minutes) during
the reaction. The starting solution was 0.2 mg/ml morphine in distilled water. To
start the reaction, MtL was added to a final concentration of 78.3 U/ml. 100µL sample
were taken and put into 900 µL of methanol (MeOH) to precipitate the enzyme. The solution
was centrifuged and the supernatant was transferred to an HPLC vial via a 0.2 µm filter.
Then the solution was measured with following HPLC conditions shown in Table 5.
Table 5: Conditions for the HPLC measurement of enzymatically oxidized morphine reaction
rate determination
Column |
Poroshell 120 EC-C18 3.0 x 0.5mm |
Flow |
0.8 ml/min |
Isocratic |
85% mQ H2O, 5% MeOH, 10% formic acid |
Injection volume |
5 µL |
Column temperature |
40°C |
Signal wave length |
240 nm |
[0083] The result of the HPLC measurement is shown in Figure 9. It is clearly visible that
morphine is converted by the laccase. After 15 minutes no morphine signal was measured
anymore. This means after approx. 15 minutes 100% of the morphine was converted to
a partly precipitated product. Further analysis of the exact reaction mechanism and
reaction product has to be investigated.
[0084] In addition to the HPLC method, a GC-MS method was established and the samples were
analysed using the following conditions shown in Table 6.
Table 6: GC-MS conditions for enzymatically oxidized morphine reaction rate determination
Column |
Agilent Technologies DB17MS |
Temperature program |
120°C - 320°C |
Run time |
11.5 min |
[0085] The MS spectrum in Figure 10 shows the result of the GC-MS measurement of morphine
after the reaction. The sharp peak to the right represents morphine, which is confirmed
by the MS spectrum library shown in figure 11. This is the proof that morphine was
detected.
[0086] In Figure 12 the conversion rate of the reaction of morphine and laccase from
Myceliophthora thermophila is shown. For this reaction a concentration of 2 mg/ml morphine in distilled water
was used. To start the reaction MtL was added to a final concentration of 78.3 U/ml.
For the sample preparation 100 µL sample were taken and added to 900 µL of methanol
(MeOH) to precipitate the enzyme. The solution was centrifuged and the supernatant
was transferred to an HPLC vial via a 0.2 µm filter. In the vial there was NaSO
4 to bind remaining water from the enzyme which could cause problems in the GC chromatograph.
[0087] The conversion rate, compared to the conditions of the ones mentioned above measured
by HPLC, is much slower. After 30 minutes approx. 60% of the morphine is converted.
The cause for this is most likely the different enzyme/substrate ratio. For the HPLC
measurement, much more enzyme was used compared to the samples that were prepared
for the GC measurement. This shows that it is possible to influence the conversion
rate with the proportion of enzyme to substrate.
7. Hydrogel
[0088] According to a preferred embodiment, the compositions according to the present inventions
are provided as hydrogels. This involves the inclusion of another abuse deterrent
approach, namely to create a system which changes the rheological properties of the
reaction solution, i.e. the formation of a hydrogel. Hydrogels are very viscous and
as a consequence, the drawing up with a needle is not possible. For this purpose different
set ups were tried as shown in Table 7. The substances were mixed together until a
gel was formed.
[0089] The first trial with chitosan formed a hydrogel after approx. 15 minutes. The idea
is that catechol crosslinks the chitosan molecules and that the morphine is covalently
imbedded via Michael's type reactions. This trial was a successful proof of concept
while catechol needs to be replaced with other molecules already used as drug additives.
[0090] The second trial with carboxymethylchitosan formed a hydrogel just with morphine
after approx. 24h. This system would be non-harmful and the reaction time can be optimized.
Table 7: Conditions for enzymatic crosslinked hydrogels
Substances |
Viscosity increased |
Chitosan 2% (w/v) + 500 µM Catechol |
+ (after 15 min) |
+ morphine 10 mg/ml + 2U/ml MtL |
|
Carboxymethylchitosan 2% (w/v) |
+ (after 24 hours) |
+ morphine 10mg/ml + 2U MtL |
|
[0091] Fig. 13 shows the chitosan-catechol-morphine hydrogel Figure 14 shows the carboxymethylchitosan-morphine
hydrogel. Both hydrogels are not injectable again and cannot be used anymore for administration.
Discussion:
[0092] This study demonstrates an entirely new enzymatic approach for the development of
abuse deterrent opioids. Tapentadol and morphine were successfully converted by the
enzyme laccase which was confirmed by oxygen consumption measurements, TLC, HPLC-MS,
FTIR and GC-MS analysis.
[0093] Since the enzymatic conversion of morphine was quite straight forward, this reaction
was chosen as a model for further analysis. The reaction rate of the laccase from
Myceliophthora thermophila on morphine was analysed via HPLC and GC measurement. After
approx. 15 minutes 100% of morphine was converted to a product which precipitated.
The precipitated reaction product was analysed via FTIR and also solubility tests
were conducted. The precipitate was hardly soluble in any of the used solvents, which
is desired for abuse prevention.
[0094] Overall the desired abuse prevention system based on enzyme polymerization was successfully
developed. According to the presented results it is plausible that the present system
is extendable in principle to all drugs, especially all opioids that have a laccase-reactive
functional group.
II. Inactivation of oxycodone with an enzyme system consisting of peroxidase/laccase
[0095] Opioids are an important component of modern pain management, though the abuse and/or
misuse of those drugs have created a growing public health problem. To counteract
this problem, there is a strong demand for new technologies for preventing the abuse
of opioids. This project therefore tries to approach this problem with a very unique
way based on using enzymes.
[0096] The potential of enzymes to polymerize opioids, thereby preventing abuse was investigated.
These enzymes will not be active when opioids are administrated correctly. These possibilities
are thoroughly investigated by the present project.
[0097] In the present example, the development of an appropriate enzyme system to eliminate
opioids from solution is shown. A peroxidase is used to produce an hydroxyl group
in oxycodone while the such "activated" molecule is further transformed by the laccase.
Moreover, optimized reaction conditions for effective conversion of the opioid solution
preventing administration through injection are provided. Finally, the function of
the system is verified by showing the inactivation of the opioid destroying enzymes
proteolytically when the drugs are administered as foreseen.
Materials
[0098] The opioid that was investigated was oxycodone.
[0099] To achieve the elimination of oxycodone, the following enzymes were used: the horseradish
peroxidase and a laccase originating from
Myceliophthora thermophila (MtL). Glucose Oxidase (GOD, from Aspergillus niger) was used to generate H
2O
2 which is required for the peroxidase reaction.
Oxygen Measurements
[0100] To determine whether the laccase act on activated oxycodone an optical oxygen sensor
was used. Laccases use oxygen as electron acceptor, consequently the oxygen concentration
decreases upon substrate oxidation.
[0101] The conditions for the following reactions are shown in Table 1:
Enzyme HRP |
10 U/ml |
Enzyme Glucose Oxidase |
20 U/ml |
Enzyme Laccase |
25 U/ml |
Oxycodone |
10 mg/ml |
Glucose |
10 mg/ml |
Solvent |
Distilled water |
Temperature |
Room temperature |
Measurements of enzymatic conversion using HPLC
[0102] The kinetic of the enzymatic conversion of morphine was analyzed via HPLC-MS analysis.
[0103] Samples were taken at different time points (0, 2, 5, 10, 15, 30 minutes) during
the reaction. 500 µL samples were taken and put into 500 µL of methanol (MeOH) to
precipitate the enzyme. The solution was centrifuged using Vivaspin 500 and transferred
to an HPLC vial. Then the solution was measured with following HPLC conditions shown
in Table 2:
Table 2: Conditions for the HPLC-MS measurement of enzymatically oxidized oxycodone
reaction rate determination
Column |
Agilent Technologies ZORBAX HILIC plus |
Flow |
0.4 ml/min |
Gradient |
from 100% buffer 65mM ammonia formiate pH 3 in MQ (18,2M) to 100% ACN within 15 min;
total run 20min |
Injection volume |
1 µL |
Column temperature |
40°C |
Detection |
via MS-TOF in pos. mode |
[0104] The result can be evaluated by HPLC-MS measurement. From these data it will be clearly
visible that oxycodone is converted enzymatically to a partly precipitated product.
Further analysis of the exact reaction mechanism and reaction product is performed
with the following methods: GPC and NMR.
Hydrogel
[0105] According to a preferred embodiment, the compositions according to the present inventions
are provided as hydrogels. This involves the inclusion of another abuse deterrent
approach, namely to create a system which changes the rheological properties of the
reaction solution, i.e. the formation of a hydrogel. Hydrogels are very viscous and
as a consequence, the drawing up with a needle is not possible.
Discussion
[0106] This study demonstrates an entirely new enzymatic approach for the development of
abuse deterrent opioids. Oxycodone was successfully converted by the enzymes HRP and
laccase (with cofactor generation by glucose oxidase), which was confirmed by oxygen
consumption measurements and HPLC-MS analysis.
[0107] The reaction rate of the enzymes on oxycodone was analyzed via HPLC-MS measurement.
Oxycodone was converted to a product which precipitated.
[0108] Overall the desired abuse prevention system based on enzyme polymerization was successfully
developed. From the present results it is plausible that the present system is extendable
in principle to all drugs, especially all opioids that have a laccase-reactive functional
group.
[0109] III. Enzyme assays for selected and preferred oxycodone-processing enzymes are well
known and available for most of the preferred enzymes listed herein. As an example,
a known assay set-up for 2-oxoglutarate-dependent O-Demethylation is described hereinafter
for illustrative reasons:
O-Demethylation (2-oxoglutarate-dependent)
[0110] The direct enzyme assay for 2-oxoglutarate-dependent dioxygenase activity can be
performed using a reaction mixture of 100 mM Tris-HCl (pH 7.4), 10% (v/v) glycerol,
14 mM 2-mercaptoethanol, 1 mM alkaloid, 10 mM 2-oxoglutarate, 10 mM sodium ascorbate,
0.5 mM FeSO
4, and up to 100 µg of purified recombinant enzyme. Assays are carried out at 30°C
for 1 or 4 hours, stopped by immersing the reaction tube in boiling water for 5 min,
and subjected to LC-MS/MS analysis. 2-Oxoglutaratedependent dioxygenase activity is
also assayed using an indirect method based on the
O-demethylation-coupled decarboxylation of [1-
14C] 2-oxoglutarate. Briefly, the standard assay contained 10 µM of a 10% mole/mole
(n/n) solution of [1-
14C]2-oxoglutarate (specific activity 55 mCi/mmol) diluted with 90% n/n unlabeled 2-oxoglutarate,
10 µM unlabelled alkaloid substrate, 10 mM sodium ascorbate, 0.5 mM iron sulfate,
and 5 µg purified enzyme in a 500 µl buffered (100 mM Tris-HCl, 10% [v/v] glycerol,
14 mM 2-mercaptoethanol, pH 7.4) reaction. Assays are initiated by the addition of
enzyme, incubated for 45 min at 30°C, and stopped by removing the
14CO
2-trapping glass fiber filters (Whatman grade GF/D, pretreated with NCS-II tissue solubilizer,
Amersham Biosciences) from the reaction vial. For enzyme kinetic analyses, 10 µM of
a 1% (n/n) solution of [1-
14C]2-oxoglutarate (specific activity 55 mCi/mmol) diluted with 99% (n/n) unlabeled
2-oxoglutarate is used. Results from assays lacking an alkaloid substrate are subtracted
from corresponding assays containing alkaloid substrates to account for the uncoupled
consumption of 2-oxoglutarate. Kinetic data for e.g. T6ODM can be obtained by varying
the substrate concentrations in the reaction between 1 and 500 µM at a constant 2-oxoglutarate
concentration of 500 µM. Conversely, the 2-oxoglutarate concentration can be varied
between 1 and 500 µM at a constant substrate concentration of 30 µM, which produces
the maximum reaction velocity. Kinetic data for e.g. CODM can be obtained by varying
the 500 µM, and varying the 2-oxoglutarate concentration between 1 and 500 µM at a
constant codeine concentration of 50 µM. Saturation curves and kinetic constants can
be calculated based on Michaelis-Menten kinetics using FigP v. 2.98 (BioSoft, Cambridge,
UK; http://www.biosoft.com). The release of formaldehyde upon alkaloid O-demethylation
can be monitored using a fluorescence-based modification of the Nash assay. Nash reagent
is prepared by adding 0.3 ml of glacial acetic acid and 0.2 ml acetyl acetone to 100
ml of 2 M ammonium acetate. Enzyme assays can be performed as described above, except
that unlabelled 2-oxoglutarate is used and the reactions are quenched by the addition
of 2 volumes of Nash reagent, followed by a 10 min incubation period at 60°C to convert
formaldehyde to diacetyldihydrolutidine (DDL). The fluorescence of DDL can be recorded
using a Cary Eclipse fluorescence spectrophotometer (Varian; www.varianinc.com) at
λ
ex = 412 nm and λ
em = 505 nm. The acylcyclohexanediones, prohexadione calcium or trinexapac-ethyl, can
be tested as possible enzyme inhibitors at concentrations up to 500 µM using 100 µM
2-oxoglutarate in a standard assay.
Preferred embodiments:
[0111] The present invention therefore relates to the following preferred embodiments:
- 1. Abuse-deterrent pharmaceutical composition comprising a drug with an enzyme-reactive
functional group, wherein the drug has an abuse potential, and an enzyme capable of
reacting with the enzyme-reactive functional group (a drug-processing enzyme), wherein
the drug with the enzyme-reactive functional group is contained in the pharmaceutical
composition in a storage stable, enzyme-reactive state and under conditions wherein
no enzymatic activity acts on the drug.
- 2. Pharmaceutical composition according to embodiment 1, wherein the enzyme is selected
from the group of reductases and/or transferases and/or hydrolases, especially a monooxygenase.
- 3. Pharmaceutical composition according to embodiment 1 or 2, wherein the enzyme-reactive
functional group is a phenolic hydroxyl-group or a phenolic amino-group, preferably
a phenolic hydroxyl-group.
- 4. Pharmaceutical composition according to any one of embodiments 1 to 3, wherein
the enzyme catalyses O-dealkylation, preferably O-demethylation, N-dealkylation, preferably
N-demethylation, keto-reduction, N-oxidation, epoxy-hydroxylation, esterification,
de-amidation, peroxigenation, or dehalogenation of the drug or addition of molecules,
especially glucuronidation, sulfation and acetylation, to the drug.
- 5. Pharmaceutical composition according to any one of embodiments 1 to 4, wherein
the enzyme is selected from the group of 3-alpha-hydroxysteroid 3-dehydrogenase (EC
1.1.1.213), cytochrome P450 (EC 1.14), especially non-heme iron-dependent monooxygenase
(EC 1.14.16), copper-dependent monooxygenases (EC 1.14.17 and EC 1.14.18), the CYP2C
subfamily; CYP2D6; unspecific monooxygenase (EC 1.14.14.1), Codeine 3-O-demethylase
(CODM; EC 1.14.11.32), CYP1-3 (EC 1.14.14.1), preferably CYP3A, CYP1A, CYP2B, CYP2C
and CYP2D, especially CYP3A4, CYP3A5, CYP3A7, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and
CYP2D6; peroxidases (EC 1.11.1 und EC 1.11.2), preferably horseradish peroxidase (EC
1.11.1.7) and fungal unspecific peroxygenase (EC 1.11.2.1); carbonyl reductase (NADPH)
(EC 1.1.1.184), preferably dihydromorphinine ketone reductase (DMKR; types I to V),
dihydrocodeinone ketone reductase (DCKR, types I and II) or morphine 6-dehydrogenase
(EC 1.1.1.218); flavin-dependent monooxygenases (EC 1.13.12 and EC 1.14.13), especially
flavin-containing monooxygenase (EC 1.14.13.8); microsomal epoxide hydrolase (EC 3.3.2.9),
cofactor-independent monooxygenase; epoxide hydratase (EC 3.3.2.3 and 4.2.1.63), and
soluble epoxide hydrolase (EC 3.3.2.10); UDP-glucuronosyltransferase (EC 2.4.1.17),
preferably UGT1 and UGT2 enzymes, especially UGT1.1 and UGT2B7; bilirubin-glucuronoside
glucuronosyltransferase (EC 2.4.1.95); ac(et)yltransferase (EC 2.3), sulfotransferases
(EC 2.8.2), CoA-transferase (EC 2.8.3), especially N-acetyltransferase (NAT, EC 2.3.1)
and O-acetyltransferase (OAT; EC 2.3.1).
- 6. Pharmaceutical composition according to any one of embodiments 1 to 5, wherein
the drug is an opioid drug with an enzyme-reactive functional group, preferably selected
from the group morphine, tapentadol, oxycodone, buprenorphine, cebranopadol, diamorphine
(=heroin), dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, methadone and
levomethadone, oxymorphone, pentazocine, pethidine, fentanyl, levorphanol and levomethorphane
and pharmaceutically acceptable salts, esters, prodrugs and mixtures thereof, especially
oxycodone or morphine.
- 7. Pharmaceutical composition according to any one of embodiments 1 to 6, wherein
the composition comprises a drug/enzyme combination selected from morphine/laccase,
tapentadol/laccase, oxymorphone/laccase, hydromorphone/laccase, pentazocine/laccase,
buprenorphine/laccase, levorphanol/laccase, oxycodone/laccase/oxycodone-processing
enzyme.
- 8. Pharmaceutical composition according to any one of embodiments 1 to 7, wherein
the pharmaceutical composition is selected from a tablet, a coat-core tablet, a bi-layer
tablet, a multi-layer tablet, a sublingual and a buccal tablet, a sublingual film,
a capsule, a pellet, a MUPS (multiple unit pellet system), a granulate, a powder,
especially coated, sugar-coated and/or enteric-coated forms thereof.
- 9. Pharmaceutical composition according to any one of embodiments 1 to 8, wherein
the drug is contained in an amount of 0.1 to 5.000 mg, preferably 0.5 to 1.000 mg,
especially 1 to 500 mg, per dosage unit.
- 10. Pharmaceutical composition according to any one of embodiments 1 to 9, wherein
the enzyme is contained in an amount of 1 to 1.000 units, preferably 10 to 100 units.
- 11. Pharmaceutical composition according to any one of embodiments 1 to 10, wherein
the composition comprises a further abuse-deterrent feature, preferably selected from
the group a physical or chemical barrier, especially increased tablet hardness, a
drug antagonist, an aversion component, an abuse-deterrent delivery system and a prodrug,
especially a physical barrier or an aversion component, especially a gelling agent
and/or a non-gelling viscosity-increasing agent.
- 12. Pharmaceutical composition according to any one of embodiments 1 to 11, wherein
the composition comprises co-factors of the enzyme, preferably H and/or electron donors
and acceptors, especially NAD(P)H, FMN, FAD, ferredoxin, 2-oxoglutarate, and/or hemes;
or donors for the groups to be added to the drug, especially acetyl-Coenzyme A (ac-CoA)
or UDP-glucuronate.
- 13. Pharmaceutical composition according to any one of embodiments 1 to 12, wherein
the composition comprises a matrix containing 1 to 80 wt.% of one or more hydrophobic
or hydrophilic polymers, preferably a matrix comprising agar, alamic acid, alginic
acid, carmellose, carboxymethylcellulose sodium, carbomer, carrageenan, chitosan,
especially carboxymethylchitosan, catechol , copovidone, dextrin, gelatin, guar gum,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic
acid copolymers, methylcellulose derivatives, microcrystalline cellulose, polyacrylic
acid, polyalkylene oxide, especially polyethylene glycol, polyvinyl alcohol, polyvinyl
acetate, povidone, propylene glycol alginate, a polyvinylcaprolactam-polyvinyl acetate-polyethylene
glycol graft co-polymer, pullulan, silicon dioxide, sodium alginate, starch, vinylpyrrolidone-vinyl
acetate copolymers, xanthan gum; or of a non-polymer matrix former, preferably microcrystalline
wax, fatty alcohols and fatty acids, especially stearyl alcohol, cetyl stearyl alcohol,
stearic acid, palmitic acid or salts and mixtures thereof, mono-, di- and triglycerides
of saturated fatty acids with a chain length between 16 and 22 carbon atoms and a
mixture of such mono- di- and triglycerides.
- 14. Pharmaceutical composition according to any one of embodiments 1 to 13, wherein
the composition is storage stable, preferably by comprising less than 5%, especially
less than 1%, enzyme-processed drug after 6 month storage at 25°C under dry conditions.
- 15. Pharmaceutical composition according to any one of embodiments 1 to 14, wherein
the enzyme is acid-labile.
- 16. Pharmaceutical composition according to any one of embodiments 1 to 15, further
comprising a hydrogel-forming component and/or a crosslinker, preferably chitosan
and/or catechol or carboxymethylchitosan and/or vanillin.
- 17. Pharmaceutical composition according to any one of embodiments 1 to 16, wherein
the composition is a modified release composition, especially a prolonged release
composition.
- 18. Pharmaceutical composition according to any one of embodiments 1 to 17, comprising
a further enzyme, preferably a further drug-processing enzyme or an enzyme further
processing the processed drug forms, especially laccase (EC 1.10.3.2).
- 19. Pharmaceutical composition according to any one of embodiments 1 to 18, wherein
the drug is an opioid drug with a laccase-reactive functional group, preferably selected
from the group morphine, tapentadol, hydromorphone, desomorphine, oxymorphone, buprenorphine,
opioid peptides comprising a phenylalanine residue, such as adrenorphin, amidorphin,
casomorphin, DADLE ([D-Ala2, D-Leu5]-Enkephalin), DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), dermorphin, endomorphin, morphiceptin, and TRIMU 5 (L-tyrosyl-N-{[(3-methylbutyl)amino]acetyl}-D-alaninamide);
oripavine, 6-MDDM (6-methylenedihydrodesoxymorphine), chlornaltrexamine, dihydromorphine,
hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378 (7,8-Dihydro-14-hydroxy-N-phenethylnormorphine),
heterocodeine, dihydroheterocodeine, 7-spiroindanyloxymorphone, morphinone, pentamorphone,
semorphone, chloromorphide, nalbuphine, oxymorphazone, 1-iodomorphine, morphine-6-glucuronide,
6-monoacetylmorphine, normorphine, morphine-N-oxide, cyclorphan, dextrallorphan, levorphanol,
levophenacylmorphan, norlevorphanol, oxilorphan, phenomorphan, furethylnorlevorphanol,
xorphanol, butorphanol, 6,14-endoethenotetrahydrooripavine, BU-48 (N-Cyclopropylmethyl-[7α,8α,2',3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine),
, cyprenorphine, dihydroetorphine, etorphine, norbuprenorphine, 5'-guanidinonaltrindole,
diprenorphine, levallorphan, meptazinol, methylnaltrexone, nalfurafine, nalmefene,
naloxazone, naloxone, nalorphine, naltrexone, naltriben, naltrindole, 6β-naltrexol-d4,
pseudomorphine, naloxonazine, norbinaltorphimine, alazocine, bremazocine, dezocine,
ketazocine, metazocine, pentazocine, phenazocine, cyclazocine, hydroxypethidine (bemidone),
ketobemidone, methylketobemidone, propylketobemidone, alvimopan, picenadol and pharmaceutically
acceptable salts, esters, prodrugs and mixtures thereof, more preferred morphine,
tapentadol, buprenorphine especially morphine.
- 20. Pharmaceutical composition according to any one of embodiments 1 to 19, wherein
the drug is an opioid drug selected from the group consisting of morphine, tapentadol,
hydromorphone, desomorphine, oxymorphone, buprenorphine, opioid peptides comprising
a phenylalanine residue, such as adrenorphin, amidorphin, casomorphin, DADLE ([D-Ala2, D-Leu5]-Enkephalin), DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), dermorphin, endomorphin, morphiceptin, and TRIMU 5 (L-tyrosyl-N-{[(3-methylbutyl)amino]acetyl}-D-alaninamide);
oripavine, 6-MDDM (6-methylenedihydrodesoxymorphine), chlornaltrexamine, dihydromorphine,
hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378 (7,8-Dihydro-14-hydroxy-N-phenethylnormorphine),
heterocodeine, dihydroheterocodeine, 7-spiroindanyloxymorphone, morphinone, pentamorphone,
semorphone, chloromorphide, nalbuphine, oxymorphazone, 1-iodomorphine, morphine-6-glucuronide,
6-monoacetylmorphine, normorphine, morphine-N-oxide, cyclorphan, dextrallorphan, levorphanol,
levophenacylmorphan, norlevorphanol, oxilorphan, phenomorphan, furethylnorlevorphanol,
xorphanol, butorphanol, 6,14-endoethenotetrahydrooripavine, BU-48 (N-Cyclopropylmethyl-[7a,8a,2',3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine),
cyprenorphine, dihydroetorphine, etorphine, norbuprenorphine, 5'-guanidinonaltrindole,
diprenorphine, levallorphan, meptazinol, methylnaltrexone, nalfurafine, nalmefene,
naloxazone, naloxone, nalorphine, naltrexone, naltriben, naltrindole, 6β-naltrexol-d4,
pseudomorphine, naloxonazine, norbinaltorphimine, alazocine, bremazocine, dezocine,
ketazocine, metazocine, pentazocine, phenazocine, cyclazocine, hydroxypethidine (bemidone),
ketobemidone, methylketobemidone, propylketobemidone, picenadol, codeine, thebaine,
diacetylmorphine (morphine diacetate; heroin) nicomorphine (morphine dinicotinate),
dipropanoylmorphine (morphinedipropionate), diacetyldihydromorphine, acetylpropionylmorphine,
dibenzoylmorphine, dihydrocodeine, ethylmorphine, hydrocodone, oxycodone, fentanyl,
α-methylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl,
pethidine (meperidine), MPPP, allylprodine, α-prodine, PEPAP, propoxyphene, dextropropoxyphene,
dextromoramide, bezitramide, piritramide, methadone, levomethadone, pethidine, dipipanone,
levomethadyl acetate (LAAM), difenoxin, diphenoxylate, levomethorphan, dextromethorphan,
lefetamine, mitragynine, tilidine, tramadol, eluxadoline, 2,4-dinitrophenylmorphine,
dihydroheroin, 6-MAC, benzylmorphine, codeine methylbromide, pholcodine, myrophine,
8-CAC, 4-fluoromeperidine, allylnorpethidine, anileridine, benzethidine, carperidine,
etoxeridine, furethidine, morpheridine, oxpheneridine, pheneridine, phenoperidine,
piminodine, properidine, sameridine, α-meprodine, prosidol, trimeperidine, acetoxyketobemidone,
droxypropine, dipipanone, normethadone, phenadoxone, dimepheptanol, levacetylmethadol,
dextromoramide, levomoramide , racemoramide, diethylthiambutene, dimethylthiambutene,
ethylmethylthiambutene, piperidylthiambutene, pyrrolidinylthiambutene, thiambutene,
tipepidine, dimenoxadol, dextropropoxyphene, levopropoxyphene, norpropoxyphene, dioxaphetyl
butyrate, diampromide, phenampromide, propiram, methiodone, isoaminile, lefetamine,
R-4066, 3-allylfentanyl, 3-methylfentanyl, 4-phenylfentanyl, alfentanil, α-methylacetylfentanyl,
β-hydroxyfentanyl, β-hydroxythiofentanyl, β-methylfentanyl, brifentanil, lofentanil,
mirfentanil, ocfentanil, parafluorofentanyl, phenaridine, thiofentanyl, trefentanil,
ethoheptazine, metheptazine, metethoheptazine, proheptazine, bezitramide, piritramide,
clonitazene, etonitazene, 18-MC, 7-hydroxymitragynine, akuammine, eseroline, hodgkinsine,
mitragynine, pericine, BW373U86, DPI-221, DPI-287, DPI-3290, SNC-80, AD-1211, AH-7921,
azaprocin, bromadol, BRL-52537, bromadoline, C-8813, ciramadol, doxpicomine, enadoline,
faxeladol, GR-89696, herkinorin, ICI-199441, ICI-204448, J-113397, JTC-801, LPK-26,
methopholine, MT-45 and pharmaceutically acceptable salts, hydrates, solvates, esters,
prodrugs and mixtures thereof, more preferred morphine, oxycodone, tapentadol, buprenorphine,
cebranopadol, diamorphine (=heroin), dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone,
methadone and levomethadone, oxymorphone, pentazocine, pethidine, fentanyl, levorphanol
and levomethorphane, especially oxycodone and morphine.
- 21. Pharmaceutical composition according to any one of embodiments 1 to 20, wherein
the composition renders immediate release, modified release, or a combination thereof.
- 22. Pharmaceutical composition according to any one of embodiments 1 to 21, wherein
the composition comprises an opioid analgesic alone or in combination with a non-opioid
analgesic, especially with ibuprofen, diclofenac, naproxen, paracetamol and acetyl-salicylic
acid.
- 23. Method for manufacturing a pharmaceutical composition according to any one of
embodiments 1 to 22 comprising the steps of mixing the drug with the enzyme and finishing
the mixture to a pharmaceutical composition.
- 24. Method for manufacturing a pharmaceutical composition according to any one of
embodiments 1 to 22 comprising the steps of providing the drug and the enzyme in separated
form and finishing the separated drug and enzyme to a pharmaceutical composition.
- 25. Pharmaceutical composition according to any one of embodiments 1 to 22 for use
in the treatment of drug addiction.
- 26. Pharmaceutical composition according to any one of embodiments 1 to 22 for use
in the treatment of pain.
- 27. Pharmaceutical composition according to any one of embodiments 1 to 22, wherein
the drug-processing enzyme essentially does not act on the drug in vivo when the composition
is swallowed intact.
- 28. Pharmaceutical composition according to any one of embodiments 1 to 22, wherein
the drug-processing enzyme exists in the formulation in an essentially non-releasable
form when the composition is swallowed intact.
- 29. Pharmaceutical composition according to any one of embodiments 1 to 22, wherein
the drug-processing enzyme is deactivated in vivo.
1. Abuse-deterrent pharmaceutical composition comprising a drug with an enzyme-reactive
functional group, wherein the drug has an abuse potential, and an enzyme capable of
reacting with the enzyme-reactive functional group (a drug-processing enzyme), wherein
the drug with the enzyme-reactive functional group is contained in the pharmaceutical
composition in a storage stable, enzyme-reactive state and under conditions wherein
no enzymatic activity acts on the drug.
2. Pharmaceutical composition according to claim 1, wherein the enzyme is selected from
the group of reductases and/or transferases and/or hydrolases, especially a monooxygenase.
3. Pharmaceutical composition according to claim 1 or 2, wherein the enzyme-reactive
functional group is a phenolic hydroxyl-group or a phenolic amino-group, preferably
a phenolic hydroxyl-group.
4. Pharmaceutical composition according to any one of claims 1 to 3, wherein the enzyme
catalyses O-dealkylation, preferably O-demethylation, N-dealkylation, preferably N-demethylation,
keto-reduction, N-oxidation, epoxy-hydroxylation, esterification, de-amidation, peroxigenation,
or dehalogenation of the drug or addition of molecules, especially glucuronidation,
sulfation and acetylation, to the drug.
5. Pharmaceutical composition according to any one of claims 1 to 4, wherein the enzyme
is selected from the group of 3-alpha-hydroxysteroid 3-dehydrogenase (EC 1.1.1.213),
cytochrome P450 (EC 1.14), especially non-heme iron-dependent monooxygenase (EC 1.14.16),
copper-dependent monooxygenases (EC 1.14.17 and EC 1.14.18), the CYP2C subfamily;
CYP2D6; unspecific monooxygenase (EC 1.14.14.1), Codeine 3-O-demethylase (CODM; EC
1.14.11.32), CYP1-3 (EC 1.14.14.1), preferably CYP3A, CYP1A, CYP2B, CYP2C and CYP2D,
especially CYP3A4, CYP3A5, CYP3A7, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6; peroxidases
(EC 1.11.1 und EC 1.11.2), preferably horseradish peroxidase (EC 1.11.1.7) and fungal
unspecific peroxygenase (EC 1.11.2.1); carbonyl reductase (NADPH) (EC 1.1.1.184),
preferably dihydromorphinine ketone reductase (DMKR; types I to V), dihydrocodeinone
ketone reductase (DCKR, types I and II) or morphine 6-dehydrogenase (EC 1.1.1.218);
flavin-dependent monooxygenases (EC 1.13.12 and EC 1.14.13), especially flavin-containing
monooxygenase (EC 1.14.13.8); microsomal epoxide hydrolase (EC 3.3.2.9), cofactor-independent
monooxygenase; epoxide hydratase (EC 3.3.2.3 and 4.2.1.63), and soluble epoxide hydrolase
(EC 3.3.2.10); UDP-glucuronosyltransferase (EC 2.4.1.17), preferably UGT1 and UGT2
enzymes, especially UGT1.1 and UGT2B7; bilirubin-glucuronoside glucuronosyltransferase
(EC 2.4.1.95); ac(et)yltransferase (EC 2.3), sulfotransferases (EC 2.8.2), CoA-transferase
(EC 2.8.3), especially N-acetyltransferase (NAT, EC 2.3.1) and O-acetyltransferase
(OAT; EC 2.3.1).
6. Pharmaceutical composition according to any one of claims 1 to 5, wherein the drug
is an opioid drug with an enzyme-reactive functional group, preferably selected from
the group morphine, tapentadol, oxycodone, buprenorphine, cebranopadol, diamorphine
(=heroin), dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, methadone and
levomethadone, oxymorphone, pentazocine, pethidine, fentanyl, levorphanol and levomethorphane
and pharmaceutically acceptable salts, esters, prodrugs and mixtures thereof, especially
oxycodone or morphine.
7. Pharmaceutical composition according to any one of claims 1 to 6, wherein the composition
comprises a drug/enzyme combination selected from morphine/laccase, tapentadol/laccase,
oxymorphone/laccase, hydromorphone/laccase, pentazocine/laccase, buprenorphine/laccase,
levorphanol/laccase, oxycodone/laccase/oxycodone-processing enzyme.
8. Pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical
composition is selected from a tablet, a coat-core tablet, a bi-layer tablet, a multi-layer
tablet, a sublingual and a buccal tablet, a sublingual film, a capsule, a pellet,
a MUPS (multiple unit pellet system), a granulate, a powder, especially coated, sugar-coated
and/or enteric-coated forms thereof.
9. Pharmaceutical composition according to any one of claims 1 to 8, wherein the composition
is storage stable, preferably by comprising less than 5%, especially less than 1%,
enzyme-processed drug after 6 month storage at 25°C under dry conditions.
10. Pharmaceutical composition according to any one of claims 1 to 9, comprising a further
enzyme, preferably a further drug-processing enzyme or an enzyme further processing
the processed drug forms, especially laccase (EC 1.10.3.2).
11. Pharmaceutical composition according to any one of claims 1 to 10, wherein the drug
is an opioid drug with a laccase-reactive functional group, preferably selected from
the group morphine, tapentadol, hydromorphone, desomorphine, oxymorphone, buprenorphine,
opioid peptides comprising a phenylalanine residue, such as adrenorphin, amidorphin,
casomorphin, DADLE ([D-Ala2, D-Leu5]-Enkephalin), DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), dermorphin, endomorphin, morphiceptin, and TRIMU 5 (L-tyrosyl-N-{[(3-methylbutyl)amino]acetyl}-D-alaninamide);
oripavine, 6-MDDM (6-methylenedihydrodesoxymorphine), chlornaltrexamine, dihydromorphine,
hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378 (7,8-Dihydro-14-hydroxy-N-phenethylnormorphine),
heterocodeine, dihydroheterocodeine, 7-spiroindanyloxymorphone, morphinone, pentamorphone,
semorphone, chloromorphide, nalbuphine, oxymorphazone, 1-iodomorphine, morphine-6-glucuronide,
6-monoacetylmorphine, normorphine, morphine-N-oxide, cyclorphan, dextrallorphan, levorphanol,
levophenacylmorphan, norlevorphanol, oxilorphan, phenomorphan, furethylnorlevorphanol,
xorphanol, butorphanol, 6,14-endoethenotetrahydrooripavine, BU-48 (N-Cyclopropylmethyl-[7α,8α,2',3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine),
, cyprenorphine, dihydroetorphine, etorphine, norbuprenorphine, 5'-guanidinonaltrindole,
diprenorphine, levallorphan, meptazinol, methylnaltrexone, nalfurafine, nalmefene,
naloxazone, naloxone, nalorphine, naltrexone, naltriben, naltrindole, 6β-naltrexol-d4,
pseudomorphine, naloxonazine, norbinaltorphimine, alazocine, bremazocine, dezocine,
ketazocine, metazocine, pentazocine, phenazocine, cyclazocine, hydroxypethidine (bemidone),
ketobemidone, methylketobemidone, propylketobemidone, alvimopan, picenadol and pharmaceutically
acceptable salts, esters, prodrugs and mixtures thereof, more preferred morphine,
tapentadol, buprenorphine especially morphine.
12. Pharmaceutical composition according to any one of claims 1 to 11, wherein the drug
is an opioid drug selected from the group consisting of morphine, tapentadol, hydromorphone,
desomorphine, oxymorphone, buprenorphine, opioid peptides comprising a phenylalanine
residue, such as adrenorphin, amidorphin, casomorphin, DADLE ([D-Ala2, D-Leu5]-Enkephalin), DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), dermorphin, endomorphin, morphiceptin, and TRIMU 5 (L-tyrosyl-N-{[(3-methylbutyl)amino]acetyl}-D-alaninamide);
oripavine, 6-MDDM (6-methylenedihydrodesoxymorphine), chlornaltrexamine, dihydromorphine,
hydromorphinol, methyldesorphine, N-phenethylnormorphine, RAM-378 (7,8-Dihydro-14-hydroxy-N-phenethylnormorphine),
heterocodeine, dihydroheterocodeine, 7-spiroindanyloxymorphone, morphinone, pentamorphone,
semorphone, chloromorphide, nalbuphine, oxymorphazone, 1-iodomorphine, morphine-6-glucuronide,
6-monoacetylmorphine, normorphine, morphine-N-oxide, cyclorphan, dextrallorphan, levorphanol,
levophenacylmorphan, norlevorphanol, oxilorphan, phenomorphan, furethylnorlevorphanol,
xorphanol, butorphanol, 6,14-endoethenotetrahydrooripavine, BU-48 (N-Cyclopropylmethyl-[7α,8α,2',3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine),
cyprenorphine, dihydroetorphine, etorphine, norbuprenorphine, 5'-guanidinonaltrindole,
diprenorphine, levallorphan, meptazinol, methylnaltrexone, nalfurafine, nalmefene,
naloxazone, naloxone, nalorphine, naltrexone, naltriben, naltrindole, 6β-naltrexol-d4,
pseudomorphine, naloxonazine, norbinaltorphimine, alazocine, bremazocine, dezocine,
ketazocine, metazocine, pentazocine, phenazocine, cyclazocine, hydroxypethidine (bemidone),
ketobemidone, methylketobemidone, propylketobemidone, picenadol, codeine, thebaine,
diacetylmorphine (morphine diacetate; heroin) nicomorphine (morphine dinicotinate),
dipropanoylmorphine (morphinedipropionate), diacetyldihydromorphine, acetylpropionylmorphine,
dibenzoylmorphine, dihydrocodeine, ethylmorphine, hydrocodone, oxycodone, fentanyl,
α-methylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl,
pethidine (meperidine), MPPP, allylprodine, α-prodine, PEPAP, propoxyphene, dextropropoxyphene,
dextromoramide, bezitramide, piritramide, methadone, levomethadone, pethidine, dipipanone,
levomethadyl acetate (LAAM), difenoxin, diphenoxylate, levomethorphan, dextromethorphan,
lefetamine, mitragynine, tilidine, tramadol, eluxadoline, 2,4-dinitrophenylmorphine,
dihydroheroin, 6-MAC, benzylmorphine, codeine methylbromide, pholcodine, myrophine,
8-CAC, 4-fluoromeperidine, allylnorpethidine, anileridine, benzethidine, carperidine,
etoxeridine, furethidine, morpheridine, oxpheneridine, pheneridine, phenoperidine,
piminodine, properidine, sameridine, α-meprodine, prosidol, trimeperidine, acetoxyketobemidone,
droxypropine, dipipanone, normethadone, phenadoxone, dimepheptanol, levacetylmethadol,
dextromoramide, levomoramide , racemoramide, diethylthiambutene, dimethylthiambutene,
ethylmethylthiambutene, piperidylthiambutene, pyrrolidinylthiambutene, thiambutene,
tipepidine, dimenoxadol, dextropropoxyphene, levopropoxyphene, norpropoxyphene, dioxaphetyl
butyrate, diampromide, phenampromide, propiram, methiodone, isoaminile, lefetamine,
R-4066, 3-allylfentanyl, 3-methylfentanyl, 4-phenylfentanyl, alfentanil, α-methylacetylfentanyl,
β-hydroxyfentanyl, β-hydroxythiofentanyl, β-methylfentanyl, brifentanil, lofentanil,
mirfentanil, ocfentanil, parafluorofentanyl, phenaridine, thiofentanyl, trefentanil,
ethoheptazine, metheptazine, metethoheptazine, proheptazine, bezitramide, piritramide,
clonitazene, etonitazene, 18-MC, 7-hydroxymitragynine, akuammine, eseroline, hodgkinsine,
mitragynine, pericine, BW373U86, DPI-221, DPI-287, DPI-3290, SNC-80, AD-1211, AH-7921,
azaprocin, bromadol, BRL-52537, bromadoline, C-8813, ciramadol, doxpicomine, enadoline,
faxeladol, GR-89696, herkinorin, ICI-199441, ICI-204448, J-113397, JTC-801, LPK-26,
methopholine, MT-45 and pharmaceutically acceptable salts, hydrates, solvates, esters,
prodrugs and mixtures thereof, more preferred morphine, oxycodone, tapentadol, buprenorphine,
cebranopadol, diamorphine (=heroin), dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone,
methadone and levomethadone, oxymorphone, pentazocine, pethidine, fentanyl, levorphanol
and levomethorphane, especially oxycodone and morphine.
13. Pharmaceutical composition according to any one of claims 1 to 12 for use in the treatment
of pain and/or drug addiction.
14. Method for manufacturing a pharmaceutical composition according to any one of claims
1 to 13 comprising the steps of mixing the drug with the enzyme and finishing the
mixture to a pharmaceutical composition.
15. Method for manufacturing a pharmaceutical composition according to any one of claims
1 to 13 comprising the steps of providing the drug and the enzyme in separated form
and finishing the separated drug and enzyme to a pharmaceutical composition.